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Liu Q, Deng G, Jiang X, Fu Y, Zhang J, Wu X, Li X, Ai J, Liu H, Tan G. Macrophage-mediated activation of the IL4I1/AhR axis is a key player in allergic rhinitis. Int Immunopharmacol 2025; 152:114439. [PMID: 40080924 DOI: 10.1016/j.intimp.2025.114439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/22/2025] [Accepted: 03/04/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND Epidemiological evidence suggests that environmental pollutants precipitate the occurrence of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR), a receptor or sensor for various contaminants, is closely related to immunomodulation and the polarization of M2 macrophages. However, the mechanisms involving AhR and M2 macrophages in AR remain unclear. METHODS Bioinformatics analysis of GEO datasets (GSE180697 and GSE180697) assessed AhR and IL4I1 expression levels, which were then verified in the nasal mucosa, monocytes and serum of patients with AR using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Primary human mononuclear cells were isolated from peripheral blood using a magnetic separation technique, and THP-1 cell lines with IL4I1 overexpression or downexpression were established through lentiviral constructs. M2 macrophages were induced with the cytokines CSF, IL4 and IL13 and then treated with the AhR agonist FICZ or inhibitor CH223191. The polarization of M2 macrophages was measured by flow cytometry and western blotting. Furthermore, primary nasal epithelial cells and macrophages were co-cultured to assess the epithelial-mesenchymal transition (EMT) in epithelial cells. The AR murine model was established using ovalbumin (OVA). Inflammation within the nasal mucosa and lung tissue was examined after CH223191 or IL4I1 treatment. RESULTS Nuclear translocation of AhR and upregulation of IL4I1 was observed in peripheral mononuclear cells and nasal mucosal tissue of patients with AR. Through the activation of AhR, IL4I1 promoted M2 macrophage polarization. Furthermore, modulation of the IL4I1/AhR axis regulated the migratory impact of OVA on T-M2 cells. The IL4I1/AhR axis was involved in the regulation of M2 macrophage-associated EMT and contributed to the expression of IL-33 and STAT6 phosphorylation in epithelial cells. In AR mice, increased AhR nuclear translocation and higher expression of IL4I1 and the M2 macrophage marker CD206 in the lungs was observed. The IL4I1/AhR axis exacerbated allergic symptoms in AR mice, fostering allergic inflammation within the nasal mucosa and lungs. CONCLUSIONS The IL4I1/AhR axis is activated within the mononuclear phagocyte system of patients with AR. This activation facilitates the polarization of mononuclear cells into M2 macrophages, which further aggravates EMT in epithelial cells and exacerbates inflammation in AR. This study may provide novel strategies for the precise treatment of AR.
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Affiliation(s)
- Qian Liu
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; Department of Otolaryngology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China
| | - Guohao Deng
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xian Jiang
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Yanpeng Fu
- Department of Otorhinolaryngology Head and Neck Surgery, Second Afliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, China
| | - Jian Zhang
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xue Wu
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xinlong Li
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Jingang Ai
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Honghui Liu
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
| | - Guolin Tan
- Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
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2
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Canè S, Geiger R, Bronte V. The roles of arginases and arginine in immunity. Nat Rev Immunol 2025; 25:266-284. [PMID: 39420221 DOI: 10.1038/s41577-024-01098-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2024] [Indexed: 10/19/2024]
Abstract
Arginase activity and arginine metabolism in immune cells have important consequences for health and disease. Their dysregulation is commonly observed in cancer, autoimmune disorders and infectious diseases. Following the initial description of a role for arginase in the dysfunction of T cells mounting an antitumour response, numerous studies have broadened our understanding of the regulation and expression of arginases and their integration with other metabolic pathways. Here, we highlight the differences in arginase compartmentalization and storage between humans and rodents that should be taken into consideration when assessing the effects of arginase activity. We detail the roles of arginases, arginine and its metabolites in immune cells and their effects in the context of cancer, autoimmunity and infectious disease. Finally, we explore potential therapeutic strategies targeting arginases and arginine.
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Affiliation(s)
- Stefania Canè
- The Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Roger Geiger
- Institute for Research in Biomedicine (IRB), Università della Svizzera italiana, Bellinzona, Switzerland
- Institute of Oncology Research (IOR), Università della Svizzera italiana, Bellinzona, Switzerland
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3
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Guan F, Wang R, Yi Z, Luo P, Liu W, Xie Y, Liu Z, Xia Z, Zhang H, Cheng Q. Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets. Signal Transduct Target Ther 2025; 10:93. [PMID: 40055311 PMCID: PMC11889221 DOI: 10.1038/s41392-025-02124-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 11/01/2024] [Accepted: 12/15/2024] [Indexed: 05/04/2025] Open
Abstract
Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.
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Affiliation(s)
- Fan Guan
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Ruixuan Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhenjie Yi
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Wanyao Liu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yao Xie
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiwei Xia
- Department of Neurology, Hunan Aerospace Hospital, Hunan Normal University, Changsha, China.
| | - Hao Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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4
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Wong A, Sun Q, Latif II, Karwi QG. Macrophage energy metabolism in cardiometabolic disease. Mol Cell Biochem 2025; 480:1763-1783. [PMID: 39198360 PMCID: PMC11842501 DOI: 10.1007/s11010-024-05099-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 08/19/2024] [Indexed: 09/01/2024]
Abstract
In a rapidly expanding body of literature, the major role of energy metabolism in determining the response and polarization status of macrophages has been examined, and it is currently a very active area of research. The metabolic flux through different metabolic pathways in the macrophage is interconnected and complex and could influence the polarization of macrophages. Earlier studies suggested glucose flux through cytosolic glycolysis is a prerequisite to trigger the pro-inflammatory phenotypes of macrophages while proposing that fatty acid oxidation is essential to support anti-inflammatory responses by macrophages. However, recent studies have shown that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully defined yet. In this review, we systematically reviewed and summarized the literature regarding the role of energy metabolism in controlling macrophage activity and how that might be altered in cardiometabolic diseases, namely heart failure, obesity, and diabetes. We critically appraised the experimental studies and methodologies in the published studies. We also highlighted the challenging concepts in macrophage metabolism and identified several research questions yet to be addressed in future investigations.
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Affiliation(s)
- Angela Wong
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, A1B 3V6, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Qiuyu Sun
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, A1B 3V6, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Ismail I Latif
- Department of Microbiology, College of Medicine, University of Diyala, Baqubaa, Diyala, Iraq
| | - Qutuba G Karwi
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, A1B 3V6, Canada.
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5
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Liu L, Li M, Zhang C, Zhong Y, Liao B, Feng J, Deng L. Macrophage metabolic reprogramming: A trigger for cardiac damage in autoimmune diseases. Autoimmun Rev 2025; 24:103733. [PMID: 39716498 DOI: 10.1016/j.autrev.2024.103733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 12/25/2024]
Abstract
Macrophage metabolic reprogramming has a central role in the progression of autoimmune and auto-inflammatory diseases. The heart is a major target organ in many autoimmune conditions and can sustain functional and structural impairments, potentially leading to irreversible cardiac damage. There is mounting clinical evidence pointing to a link between autoimmune disease and cardiac damage. However, this association remains poorly understood, and numerous patients do not receive appropriate preventive measures, which poses serious cardiovascular risks and significantly impacts their quality of life. This review discusses the relationship between macrophage metabolic reprogramming and cardiac damage in patients with autoimmune diseases and the role of adaptive immunity in macrophage reprogramming. It also provides an overview of the immunosuppressive therapies used at present. Exploiting the properties of macrophage reprogramming could lead to development of novel treatments for patients with autoimmune-related cardiac damage.
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Affiliation(s)
- Lin Liu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, Luzhou, China
| | - Minghao Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, Luzhou, China
| | - Chunyu Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, Luzhou, China
| | - Yi Zhong
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, Luzhou, China
| | - Bin Liao
- Department of Cardiovascular Surgery, The Affiliated Hospital of Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, Luzhou, China.
| | - Li Deng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, Luzhou, China; Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
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6
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Huangfu L, Wang J, Li D, Fei H, Chen X, Dong J, Sun L. Fraxetin inhibits IKKβ, blocks NF-κB pathway and NLRP3 inflammasome activation, and alleviates spleen injury in sepsis. Chem Biol Interact 2025; 408:111406. [PMID: 39921189 DOI: 10.1016/j.cbi.2025.111406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 01/01/2025] [Accepted: 01/27/2025] [Indexed: 02/10/2025]
Abstract
Sepsis is a systemic inflammatory condition associated with severe organ failure, particularly splenic injury. Fraxetin (Fra), a natural product isolated from ash bark, exhibits anti-inflammatory and antioxidant properties. This study explores the function and mechanism of Fra in sepsis-induced splenic injury using an in vivo mouse model induced by Cecal Ligation and Puncture and an in vitro sepsis model based on LPS/ATP co-stimulated J774A.1 cells. The experimental groups are as follows: Sham operation or control group, Fra control group, CLP or LPS/ATP group, CLP + Fra group or LPS/ATP + Fra group, with Dexamethasone as a positive control. The results indicated that Fra improved the survival rate, inhibited bacteria burden, and reduced spleen edema. Fra also alleviated spleen necrosis, and restored the structural integrity. Blood results showed that Fra restored platelet count and lymphocyte percentage, reduced neutrophil ratio and C-reactive protein increase, and prevented lymphocyte depletion. Immunohistochemistry demonstrated that Fra inhibited MPO levels. Additionally, Fra downregulated Procalcitonin, inhibited pro-inflammatory cytokines, NO release and Arg-1 expression, illustrating its anti-inflammatory effects. DHE staining revealed that Fra inhibited ROS and MDA, enhanced CAT, GSH-PX, and SOD activities. Furthermore, Fra inhibited NLRP3 inflammasome activation, p-IKKβ expression and NF-κB pathway. Mechanistically, molecular docking studies revealed that Fra could bind to IKKβ, thereby blocking the NF-κB pathway and NLRP3 inflammasome, functioning anti-inflammatory effects. In summary, Fra targets IKKβ to block the NF-κB pathway and NLRP3 inflammasome activation, alleviating sepsis-induced splenic injury, making it a promising therapeutic strategy for treating sepsis-induced splenic injury.
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Affiliation(s)
- Liwei Huangfu
- School of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College, Huai'an, Jiangsu, 223005, China
| | - Jing Wang
- School of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College, Huai'an, Jiangsu, 223005, China
| | - Da Li
- School of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College, Huai'an, Jiangsu, 223005, China
| | - Haiyang Fei
- School of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College, Huai'an, Jiangsu, 223005, China
| | - Xuan Chen
- School of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College, Huai'an, Jiangsu, 223005, China
| | - Jingquan Dong
- Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, Jiangsu, 222005, China.
| | - Lan Sun
- School of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College, Huai'an, Jiangsu, 223005, China.
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7
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Wang C, Liu A, Zhao Z, Ying T, Deng S, Jian Z, Zhang X, Yi C, Li D. Application and progress of 3D printed biomaterials in osteoporosis. Front Bioeng Biotechnol 2025; 13:1541746. [PMID: 39968010 PMCID: PMC11832546 DOI: 10.3389/fbioe.2025.1541746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 01/17/2025] [Indexed: 02/20/2025] Open
Abstract
Osteoporosis results from a disruption in skeletal homeostasis caused by an imbalance between bone resorption and bone formation. Conventional treatments, such as pharmaceutical drugs and hormone replacement therapy, often yield suboptimal results and are frequently associated with side effects. Recently, biomaterial-based approaches have gained attention as promising alternatives for managing osteoporosis. This review summarizes the current advancements in 3D-printed biomaterials designed for osteoporosis treatment. The benefits of biomaterial-based approaches compared to traditional systemic drug therapies are discussed. These 3D-printed materials can be broadly categorized based on their functionalities, including promoting osteogenesis, reducing inflammation, exhibiting antioxidant properties, and inhibiting osteoclast activity. 3D printing has the advantages of speed, precision, personalization, etc. It is able to satisfy the requirements of irregular geometry, differentiated composition, and multilayered structure of articular osteochondral scaffolds with boundary layer structure. The limitations of existing biomaterials are critically analyzed and future directions for biomaterial-based therapies are considered.
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Affiliation(s)
- Chenxu Wang
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
- Department of Orthopedics, The First Affiliated Hospital of Henan University, Kaifeng, China
| | - Aiguo Liu
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
- Department of Orthopedics, The First Affiliated Hospital of Henan University, Kaifeng, China
| | - Ziwen Zhao
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Ting Ying
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Shuang Deng
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Zhen Jian
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Xu Zhang
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Chengqing Yi
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Dejian Li
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
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8
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Karadima E, Chavakis T, Alexaki VI. Arginine metabolism in myeloid cells in health and disease. Semin Immunopathol 2025; 47:11. [PMID: 39863828 PMCID: PMC11762783 DOI: 10.1007/s00281-025-01038-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 01/15/2025] [Indexed: 01/27/2025]
Abstract
Metabolic flexibility is key for the function of myeloid cells. Arginine metabolism is integral to the regulation of myeloid cell responses. Nitric oxide (NO) production from arginine is vital for the antimicrobial and pro-inflammatory responses. Conversely, the arginase 1 (ARG1)-dependent switch between the branch of NO production and polyamine synthesis downregulates inflammation and promotes recovery of tissue homeostasis. Creatine metabolism is key for energy supply and proline metabolism is required for collagen synthesis. Myeloid ARG1 also regulates extracellular arginine availability and T cell responses in parasitic diseases and cancer. Cancer, surgery, sepsis and persistent inflammation in chronic inflammatory diseases, such as neuroinflammatory diseases or arthritis, are associated with dysregulation of arginine metabolism in myeloid cells. Here, we review current knowledge on arginine metabolism in different myeloid cell types, such as macrophages, neutrophils, microglia, osteoclasts, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs). A deeper understanding of the function of arginine metabolism in myeloid cells will improve our knowledge on the pathology of several diseases and may set the platform for novel therapeutic applications.
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Affiliation(s)
- Eleftheria Karadima
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Vasileia Ismini Alexaki
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.
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9
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Xiao X, Huang G, Yu X, Tan Y. Advances in Selenium and Related Compounds Inhibiting Multi-Organ Fibrosis. Drug Des Devel Ther 2025; 19:251-265. [PMID: 39830783 PMCID: PMC11742456 DOI: 10.2147/dddt.s488226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 12/03/2024] [Indexed: 01/22/2025] Open
Abstract
Selenium (Se), a critically essential trace element, plays a crucial role in diverse physiological processes within the human body, such as oxidative stress response, inflammation regulation, apoptosis, and lipid metabolism. Organ fibrosis, a pathological condition caused by various factors, has become a significant global health issue. Numerous studies have demonstrated the substantial impact of Se on fibrotic diseases. This review delves into the latest research advancements in Se and Se-related biological agents for alleviating fibrosis in the heart, liver, lungs, and kidneys, detailing their mechanisms of action within fibrotic pathways. Additionally, the article summa-rizes some of the anti-fibrotic drugs currently in clinical trials for the aforementioned organ fibroses.
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Affiliation(s)
- Xixi Xiao
- The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Minzu University, Enshi, 445000, People’s Republic of China
| | - Guoquan Huang
- Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, People’s Republic of China
- Hubei Provincial Key Laboratory of Selenium Resources and Bioapplications, Enshi, 445000, People’s Republic of China
| | - Xinqiao Yu
- Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, People’s Republic of China
| | - Yong Tan
- Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, People’s Republic of China
- Hubei Provincial Key Laboratory of Selenium Resources and Bioapplications, Enshi, 445000, People’s Republic of China
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10
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Wang C, Jalali Motlagh N, Wojtkiewicz GR, Yang H, Kim HH, Chen JW. A specific and adaptable approach to track CD206 + macrophages by molecular MRI and fluorescence imaging. Theranostics 2025; 15:1094-1109. [PMID: 39776805 PMCID: PMC11700851 DOI: 10.7150/thno.96488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 11/22/2024] [Indexed: 01/30/2025] Open
Abstract
Rationale: The mannose receptor (CD206, expressed by the gene Mrc1) is a surface marker overexpressed by anti-inflammatory and pro-tumoral macrophages. As such, CD206+ macrophages play key roles in the immune response to different pathophysiological conditions and represent a promising diagnostic and therapeutic target. However, methods to specifically target these cells remain challenging. In this study, we describe a multi-mannose approach to develop CD206-targeting fluorescent and MRI agents that specifically and sensitively detect and monitor CD206+ macrophage immune response in different disease conditions. Methods: We designed and synthesized fluorescent agents MR1-cy5 and MR2-cy5, and MRI agents Mann2-DTPA-Gd and MannGdFish. Cellular assays using pro-inflammatory and anti-inflammatory macrophages differentiated from RAW 264.7 cells were performed, and signals were detected by fluorescence microscopy and inductively coupled plasma mass spectrometry (ICP-MS) to validate specificity in vitro. In vivo specificity and efficacy of the agents were evaluated by MRI in a subcutaneous wound healing model and experimental glioma with Mrc1 +/+ without and with D-mannose treatment, Mrc1 +/-, and Mrc1 -/- mice, and in stroke. One-way ANOVA and two-way ANOVA tests were used for data analysis. P < 0.05 was considered statistically different. Results: Both in vitro fluorescence imaging with MR2-cy5, ICP-MS with Mann2-DTPA-Gd, and in vivo MRI in Mrc1 -/- mice confirmed the specificity of our approach. Mann2-DTPA-Gd MRI can track the changes of CD206+ macrophages at different stages of wound healing, correlating well with flow cytometry data using another anti-inflammatory macrophage marker (arginase-1). The specificity and efficacy of Mann2-DPTA-Gd were further validated in experimental glioma, in which Mann2-DTPA-Gd imaging detected CD206+ tumor-associated macrophages (TAMs), demonstrated significantly decreased signals in Mrc1 +/- mice and Mrc1 -/- mice, and tracked treatment changes in D-mannose-treated Mrc1 +/+ mice. Furthermore, Mann2-DTPA-Gd can report microglia/macrophages and correlate with histology in stroke. The more Gd-stable agent MannGdFish demonstrated similar efficacy as Mann2-DTPA-Gd in vivo with favorable biodistribution and pharmacokinetics. Conclusion: We have developed a fluorescent agent (MR2-cy5) and MRI agents (Mann2-DTPA-Gd and MannGdFish) with two mannose moieties that are highly specific to CD206 and can track CD206+ macrophages in disease models of wound healing, tumor, and neurological disease. Importantly, MannGdFish, with its high specificity, stability, favorable biodistribution, and pharmacokinetics, is a promising translational candidate to noninvasively monitor CD206+ macrophages in repair/regeneration and tumors in patients. In addition, with the specific binding motif to CD206, other imaging modalities and therapeutic agents could also be introduced for theranostic applications.
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Affiliation(s)
- Cuihua Wang
- Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, 02129, MA
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge St, Boston, MA
| | - Negin Jalali Motlagh
- Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, 02129, MA
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge St, Boston, MA
| | - Gregory R. Wojtkiewicz
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge St, Boston, MA
| | - Hongzhi Yang
- Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, 02129, MA
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge St, Boston, MA
| | - Hyung-Hwan Kim
- Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Boston, MA
| | - John W. Chen
- Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, 02129, MA
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge St, Boston, MA
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11
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Bohnacker S, Henkel FDR, Hartung F, Geerlof A, Riemer S, Prodjinotho UF, Salah EB, Mourão ASD, Bohn S, Teder T, Thomas D, Gurke R, Boeckel C, Ud-Dean M, König AC, Quaranta A, Alessandrini F, Lechner A, Spitzlberger B, Kabat AM, Pearce E, Haeggström JZ, Hauck SM, Wheelock CE, Jakobsson PJ, Sattler M, Voehringer D, Feige MJ, da Costa CP, Esser-von Bieren J. A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis. Sci Immunol 2024; 9:eadl1467. [PMID: 39642243 DOI: 10.1126/sciimmunol.adl1467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 11/13/2024] [Indexed: 12/08/2024]
Abstract
The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using Heligmosomoides polygyrus bakeri (Hpb), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E2 (PGE2) as a major immune regulatory mechanism of heGDH. The induction of PGE2 and other immunoregulatory factors, including IL-12 family cytokines and indoleamine 2,3-dioxygenase 1, by heGDH required p300-mediated histone acetylation, whereas the enzyme's catalytic activity suppressed the synthesis of type 2-promoting leukotrienes by macrophages via 2-hydroxyglutarate. By contrast, the induction of immunoregulatory factors involved the heGDH N terminus by potentially mediating interactions with cellular targets (CD64 and GPNMB) identified by proteomics. Type 2 cytokines counteracted suppressive effects of heGDH on host defense, indicating that type 2 immunity can limit helminth-driven immune evasion. Thus, helminths harness a ubiquitous metabolic enzyme to epigenetically target type 2 macrophage activation and establish chronicity.
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Affiliation(s)
- Sina Bohnacker
- Department of Immunobiology, Université de Lausanne, Epalinges, Switzerland
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | - Fiona D R Henkel
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | - Franziska Hartung
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | - Arie Geerlof
- Protein Expression and Purification Facility (PEPF), Institute of Structural Biology, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Sandra Riemer
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | - Ulrich F Prodjinotho
- Institute for Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany
- Center for Global Health, Technical University of Munich, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Eya Ben Salah
- Department of Immunobiology, Université de Lausanne, Epalinges, Switzerland
| | - André Santos Dias Mourão
- Protein Expression and Purification Facility (PEPF), Institute of Structural Biology, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Stefan Bohn
- Department of CryoEM Technology, Max Planck Institute of Biochemistry, Martinsried, Germany
- Cryo-Electron Microscopy Platform and Institute of Structural Biology, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Tarvi Teder
- Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institutet, Stockholm, Sweden
| | - Dominique Thomas
- Institute of Clinical Pharmacology, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Frankfurt am Main, Germany
| | - Robert Gurke
- Institute of Clinical Pharmacology, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), Frankfurt am Main, Germany
| | - Christiane Boeckel
- Institute of Computational Biology, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Minhaz Ud-Dean
- Institute of Computational Biology, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Ann-Christine König
- Metabolomics and Proteomics Core, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Alessandro Quaranta
- Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Francesca Alessandrini
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | - Antonie Lechner
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | - Benedikt Spitzlberger
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | - Agnieszka M Kabat
- Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany
| | - Edward Pearce
- Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany
| | - Jesper Z Haeggström
- Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institutet, Stockholm, Sweden
| | - Stefanie M Hauck
- Metabolomics and Proteomics Core, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Craig E Wheelock
- Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
| | - Per-Johan Jakobsson
- Department of Medicine, Division of Rheumatology, Karolinska Institutet and Karolinska University Hospital at Solna, Stockholm, Sweden
| | - Michael Sattler
- Cryo-Electron Microscopy Platform and Institute of Structural Biology, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
- Bavarian NMR-Center, Department Chemie, Technische Universität München, Garching, Germany
| | - David Voehringer
- Infektionsbiologische Abteilung, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany
| | - Matthias J Feige
- Center for Functional Protein Assemblies (CPA), Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Garching, Germany
| | - Clarissa Prazeres da Costa
- Institute for Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany
- Center for Global Health, Technical University of Munich, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Julia Esser-von Bieren
- Department of Immunobiology, Université de Lausanne, Epalinges, Switzerland
- Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
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12
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Ovestad IT, Dalen I, Soreng K, Akbari S, Lapin M, Janssen EAM, Austdal M, Munk AC, Gudlaugsson E. Gene expression levels associated with impaired immune response and increased proliferation could serve as biomarkers for women following cervical cancer screening programmes. Front Immunol 2024; 15:1507193. [PMID: 39712018 PMCID: PMC11659148 DOI: 10.3389/fimmu.2024.1507193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 11/18/2024] [Indexed: 12/24/2024] Open
Abstract
Human papilloma virus (HPV) infections vary in their oncogenic potential, and whether an infection progresses to cervical intraepithelial neoplasia (CIN) also depends on the immune response. Therefore, the aim of the present study was to explore biomarkers related to the immune system and cell proliferation, in combination with HPV classified as having high (HOP) or low oncogenic potential (LOP), that can possibly guide a more accurate identification of women following cervical cancer screening programmes in need for immediate follow-up with a biopsy. A next-generation sequencing transcriptomic immune profile analysis applied to 28 persistent CIN3 lesions and 14 normal biopsies identified four genes, the immune markers ARG1 and HLA-DQB2 and the tumour markers CDKN2A and KRT7, as possible markers for differentiating between CIN3 and normal tissue. To validate these findings, analysis of the relative gene expression of these markers by use of reverse transcriptase real-time quantitative polymerase chain reaction was performed in an independent cohort of 264 (82 normal, 64 CIN1, and 118 CIN2/CIN3) biopsies, and the data were combined with information on the HOP- or LOP-HPV identified in the biopsies. Statistical analysis was performed with receiver operating characteristic curves, reporting area under the curve (AUC) with 95% confidence intervals (CIs), and logistic regression. Statistically significantly higher median expression levels of CDKN2A (p < 0.001) and KRT7 (p = 0.045) and significantly lower expression of ARG1 (p = 0.012) were found in biopsies with HOP-HPV infections, with no difference detected for HLA-DQB2 (p = 0.82). Models using expression levels of CDKN2A (AUC, 0.91; 95% CI, 0.86-0.95), KRT7 (0.86, 0.81-0.91), or ARG1 (0.78, 0.70-0.85) together with HOP/LOP-HPV class were significantly better than HPV class alone (0.72, 0.66-0.79) in discriminating CIN2/3 versus CIN1 (p < 0.001, p < 0.001, and p = 0.014, respectively).
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Affiliation(s)
- Irene T. Ovestad
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Ingvild Dalen
- Section of Biostatistics, Department of Research, Stavanger University Hospital, Stavanger, Norway
| | - Kristiane Soreng
- National HPV Reference laboratory Department of Microbiology and Infection Control, Akershus University Hospital, Lørenskog, Norway
| | - Saleha Akbari
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Morten Lapin
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - Emiel AM Janssen
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
- Department of Chemistry, Bioscience and Environmental Technology, University of Stavanger, Stavanger, Norway
| | - Marie Austdal
- Section of Biostatistics, Department of Research, Stavanger University Hospital, Stavanger, Norway
| | - Ane Cecilie Munk
- Department of Gynaecology, Sorlandet Hospital, Kristiansand, Norway
| | - Einar Gudlaugsson
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
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13
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Hashemi Z, Hui T, Wu A, Matouba D, Zukowski S, Nejati S, Lim C, Bruzzese J, Lin C, Seabold K, Mills C, Wrath K, Wang H, Wang H, Verzi MP, Perekatt A. Epithelial-specific loss of Smad4 alleviates the fibrotic response in an acute colitis mouse model. Life Sci Alliance 2024; 7:e202402935. [PMID: 39366762 PMCID: PMC11452480 DOI: 10.26508/lsa.202402935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/27/2024] [Accepted: 09/27/2024] [Indexed: 10/06/2024] Open
Abstract
Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel disease. But the epithelial-specific contribution to mucosal healing in vivo is poorly understood. We evaluated mucosal healing in an acute dextran sulfate sodium mouse model that shows an alleviated colitis response after epithelial-specific loss of Smad4. We find that enhanced epithelial wound healing alleviates the fibrotic response. Dextran sulfate sodium caused increased mesenchymal collagen deposition-indicative of fibrosis-within a week in the WT but not in the Smad4 KO colon. The fibrotic response correlated with decreased epithelial proliferation in the WT, whereas uninterrupted proliferation and an expanded zone of proliferation were observed in the Smad4 KO colon epithelium. Furthermore, the Smad4 KO colon showed epithelial extracellular matrix alterations that promote epithelial regeneration. Our data suggest that epithelium is a key determinant of the mucosal healing response in vivo, implicating mucosal healing as a strategy against fibrosis in inflammatory bowel disease patients.
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Affiliation(s)
- Zahra Hashemi
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Thompson Hui
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Alex Wu
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - Dahlia Matouba
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Steven Zukowski
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Shima Nejati
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Crystal Lim
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Julianna Bruzzese
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Cindy Lin
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Kyle Seabold
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Connor Mills
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Kylee Wrath
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Haoyu Wang
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Hongjun Wang
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Michael P Verzi
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - Ansu Perekatt
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
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14
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Li J, Cai X, Yang Y, Mao Y, Ding L, Xue Q, Hu X, Huang Y, Sui C, Zhang Y. Macrophage MST1 protects against schistosomiasis-induced liver fibrosis by promoting the PPARγ-CD36 pathway and suppressing NF-κB signaling. PLoS Pathog 2024; 20:e1012790. [PMID: 39700261 PMCID: PMC11785294 DOI: 10.1371/journal.ppat.1012790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 01/31/2025] [Accepted: 11/28/2024] [Indexed: 12/21/2024] Open
Abstract
Schistosomiasis is characterized by egg-induced hepatic granulomas and subsequent fibrosis. Monocyte-derived macrophages play critical and plastic roles in the progression and regression of liver fibrosis, adopting different polarization phenotypes. Mammalian STE20-like protein kinase 1 (MST1), a serine/threonine kinase, has been established to act as a negative regulator of macrophage-associated inflammation. However, the specific role of MST1 in Schistosoma-induced liver fibrosis has not been fully understood. In this study, we demonstrate that macrophage MST1 functions as an inhibitor of inflammation and fibrosis following infection with Schistosoma japonicum (S. japonicum). Mice with macrophages-specific Mst1 knockout (termed Mst1△M/△M) mice developed exacerbated liver pathology, characterized by larger egg-induced granulomas, and increased fibrosis post infection. This was accompanied by enhanced production of proinflammatory cytokines (IL1B, IL6, IL23, TNFA and TGFB) and a shift in macrophage phenotype towards Ly6Chigh. Mechanistically, MST1 activation by soluble egg antigen (SEA) promoted PPARγ-mediated CD36 expression, enhancing phagocytosis and consequently upregulation of fibrolytic genes such as Arg1 and Mmps. Conversely, MST1 deletion leads to up-regulation of pro-inflammatory genes instead of fibrolytic genes in macrophages, accompanied by decreased expression of CD36 and impaired phagocytosis. Furthermore, the ablation of MST1 enhances NF-κB activation in S. japonicum-infected and SEA-stimulated macrophages, resulting in increased production of proinflammatory cytokines. Overall, our data identified MST1 as a novel regulator for egg-induced liver fibrosis via modulation of macrophage function and phenotype by CD36-mediated phagocytosis and suppression of NF-κB pathway.
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Affiliation(s)
- Jianyang Li
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, P.R. China
- The First Affiliated Hospital of Anhui medical University, Hefei, Anhui, China
- The First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Xinyuan Cai
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, P.R. China
| | - Yan Yang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, P.R. China
| | - Yulin Mao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, P.R. China
| | - Lin Ding
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, P.R. China
| | - Qian Xue
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, P.R. China
| | - Xunhao Hu
- The First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Yan Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui, Hefei, China
| | - Cong Sui
- The First Affiliated Hospital of Anhui medical University, Hefei, Anhui, China
| | - Yuxia Zhang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, P.R. China
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15
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Wang X, Liu D. Macrophage Polarization: A Novel Target and Strategy for Pathological Scarring. Tissue Eng Regen Med 2024; 21:1109-1124. [PMID: 39352458 PMCID: PMC11589044 DOI: 10.1007/s13770-024-00669-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/20/2024] [Accepted: 08/26/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND Abnormal scarring imposes considerable challenges and burdens on the lives of patients and healthcare system. Macrophages at the wound site are found to be of great concern to overall wound healing. There have been many studies indicating an inextricably link between dysfunctional macrophages and fibrotic scars. Macrophages are not only related to pathogen destruction and phagocytosis of apoptotic cells, but also involved in angiogenesis, keratinization and collagen deposition. These abundant cell functions are attributed to specific heterogeneity and plasticity of macrophages, which also add an extra layer of complexity to correlational researches. METHODS This article summarizes current understanding of macrophage polarization in scar formation and several prevention and treatment strategies on pathological scarring related to regulation of macrophage behaviors by utilizing databases such as PubMed, Google Scholar and so on. RESULTS There are many studies proving that macrophages participate in the course of wound healing by converting their predominant phenotype. The potential of macrophages in managing hypertrophic scars and keloid lesions have been underscored. CONCLUSION Macrophage polarization offers new prevention strategies for pathological scarring. Learning about and targeting at macrophages may be helpful in achieving optimum wound healing.
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Affiliation(s)
- Xinyi Wang
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Nanchang, 330006, Jiangxi, People's Republic of China
- Queen Mary Academy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Dewu Liu
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Nanchang, 330006, Jiangxi, People's Republic of China.
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16
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Shan X, Ji Z, Wang B, Zhang Y, Dong H, Jing W, Zhou Y, Hu P, Cui Y, Li Z, Yu S, Zhou J, Wang T, Shen L, Liu Y, Yu Q. Riboflavin kinase binds and activates inducible nitric oxide synthase to reprogram macrophage polarization. Redox Biol 2024; 78:103413. [PMID: 39536592 PMCID: PMC11605425 DOI: 10.1016/j.redox.2024.103413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/24/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Riboflavin kinase (RFK) is essential in riboflavin metabolism, converting riboflavin to flavin mononucleotide (FMN), which is further processed to flavin adenine dinucleotide (FAD). While RFK enhances macrophage phagocytosis of Listeria monocytogenes, its role in macrophage polarization is not well understood. Our study reveals that RFK deficiency impairs M(IFN-γ) and promotes M(IL-4) polarization, both in vitro and in vivo. Mechanistically, RFK interacts with inducible nitric oxide (NO) synthase (iNOS), which requires FMN and FAD as cofactors for activation, leading to increased NO production that alters energy metabolism by inhibiting the tricarboxylic acid cycle and mitochondrial electron transport chain. Exogenous FAD reverses the metabolic and polarization changes caused by RFK deficiency. Furthermore, bone marrow adoptive transfer from high-riboflavin-fed mice into wild-type tumor-bearing mice reprograms tumor-associated macrophage polarization and inhibits tumor growth. These results suggest that targeting RFK-iNOS or modulating riboflavin metabolism could be potential therapies for macrophage-related immune diseases.
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Affiliation(s)
- Xiao Shan
- Department of Health Management Centre & Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, China; Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
| | - Zemin Ji
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Baochen Wang
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yanan Zhang
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Hongyuan Dong
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Weijia Jing
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yanzhao Zhou
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China; University of Electronic Science and Technology of China, Chengdu 611731, China
| | - Penghui Hu
- Department of Critical Care Medicine, Department of Anesthesiology, Tianjin Institute of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yan Cui
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Zihan Li
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Sujun Yu
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Jinxue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Ting Wang
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin 300070, China
| | - Long Shen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China.
| | - Yuping Liu
- Department of Health Management Centre & Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, China.
| | - Qiujing Yu
- Department of Health Management Centre & Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, China.
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17
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Kumari M, Sharma A, Tirpude NV. Herbacetin ameliorates lipopolysaccharide-elicited inflammatory response by suppressing NLRP-3/AIM-2 inflammasome activation, PI3K/Akt/MAPKs/NF-κB redox inflammatory signalling, modulating autophagy and macrophage polarization imbalance. Mol Biol Rep 2024; 51:1159. [PMID: 39549151 DOI: 10.1007/s11033-024-10068-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 10/25/2024] [Indexed: 11/18/2024]
Abstract
BACKGROUND Herbacetin, a flavonol abundant in traditional medicines, is documented as an anti-inflammatory agent. However, information regarding its attributes on lipopolysaccharide (LPS)-induced inflammatory immunopathies has not been delineated yet. The present study aimed to comprehend herbacetin effects on LPS-induced aspects of unwarranted, non-resolving inflammation, particularly via targeting the vicious circle of oxi-inflammatory stress, autophagy-apoptosis, macrophages polarization, impaired inflammasome activation, and inflammatory cascades. METHODS AND RESULTS In-vitro model of LPS-stimulated RAW 264.7 macrophage was recapitulated to investigate different inflammatory anomalies using enzyme-linked immunosorbent assay, qRT-PCR (Real-Time Quantitative Reverse Transcription PCR), immunoblotting. Concanavalin A challenged splenocytes and in silico studies were performed to measure Tregs population and binding affinity, respectively. RESULTS Herbacetin administration caused remarkable reduction in nitric oxide, reactive oxygen species, mitochondrial membrane potential hyperpolarization, tumor necrosis factor-α, interferon-γ, interleukin-6, inducible nitric oxide synthase and ratio of M1/M2 markers (inducible nitric oxide synthase/arginase-1/macrophage scavenger receptor-1/mannose receptor C type-1) in in vitro model of persistent inflammation. Suppression of interleukins-5,17 and matrix metalloproteinases-2,3,9,13 and proliferating cell nuclear antigen, signifies its anti-inflammatory attributes. Noticeable decline in monodansylcadaverine-Lysotracker staining, caspase-6, and enhanced p62, B-cell lymphoma-2 expression indicates apoptosis-autophagosome accumulation inhibition and lysosomal destabilization. These were accompanied by reduced NLRP3 activation, caspase-1, AIM-2 expression, and interleukin-1β release. Subsequently, up-regulated activation of TLR-4, NF-κB, PI3K, Akt, ERK1/2, and JNK was decisively thwarted by herbacetin. In silico investigation signified the interaction of herbacetin with these targets. Decreased cytokines and enhanced Tregs conferred its role in extenuating inflammation facilitated by T-cells depletion. CONCLUSION Collectively, these findings comprehend attributes of herbacetin as an alternative therapeutic strategy in relieving LPS-associated chronic inflammatory disorders.
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Affiliation(s)
- Monika Kumari
- Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, P.O. Box No: 6, Palampur, HP, 176061, India
- Academy of Scientific and Innovative Research, Ghaziabad, UP, India
| | - Anamika Sharma
- Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, P.O. Box No: 6, Palampur, HP, 176061, India
| | - Narendra Vijay Tirpude
- Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, P.O. Box No: 6, Palampur, HP, 176061, India.
- Academy of Scientific and Innovative Research, Ghaziabad, UP, India.
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18
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Yao M, Li M, Peng D, Wang Y, Li S, Zhang D, Yang B, Qiu HJ, Li LF. Unraveling Macrophage Polarization: Functions, Mechanisms, and "Double-Edged Sword" Roles in Host Antiviral Immune Responses. Int J Mol Sci 2024; 25:12078. [PMID: 39596148 PMCID: PMC11593441 DOI: 10.3390/ijms252212078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/06/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
Numerous viruses that propagate through the respiratory tract may be initially engulfed by macrophages (Mφs) within the alveoli, where they complete their first replication cycle and subsequently infect the adjacent epithelial cells. This process can lead to significant pathological damage to tissues and organs, leading to various diseases. As essential components in host antiviral immune systems, Mφs can be polarized into pro-inflammatory M1 Mφs or anti-inflammatory M2 Mφs, a process involving multiple signaling pathways and molecular mechanisms that yield diverse phenotypic and functional features in response to various stimuli. In general, when infected by a virus, M1 macrophages secrete pro-inflammatory cytokines to play an antiviral role, while M2 macrophages play an anti-inflammatory role to promote the replication of the virus. However, recent studies have shown that some viruses may exhibit the opposite trend. Viruses have evolved various strategies to disrupt Mφ polarization for efficient replication and transmission. Notably, various factors, such as mechanical softness, the altered pH value of the endolysosomal system, and the homeostasis between M1/M2 Mφs populations, contribute to crucial events in the viral replication cycle. Here, we summarize the regulation of Mφ polarization, virus-induced alterations in Mφ polarization, and the antiviral mechanisms associated with these changes. Collectively, this review provides insights into recent advances regarding Mφ polarization in host antiviral immune responses, which will contribute to the development of precise prevention strategies as well as management approaches to disease incidence and transmission.
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Affiliation(s)
- Meng Yao
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China; (M.Y.); (M.L.); (D.P.); (Y.W.); (S.L.)
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Jinzhong 030801, China; (D.Z.); (B.Y.)
| | - Meilin Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China; (M.Y.); (M.L.); (D.P.); (Y.W.); (S.L.)
| | - Dingkun Peng
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China; (M.Y.); (M.L.); (D.P.); (Y.W.); (S.L.)
| | - Yijing Wang
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China; (M.Y.); (M.L.); (D.P.); (Y.W.); (S.L.)
| | - Su Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China; (M.Y.); (M.L.); (D.P.); (Y.W.); (S.L.)
| | - Ding Zhang
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Jinzhong 030801, China; (D.Z.); (B.Y.)
| | - Bo Yang
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Jinzhong 030801, China; (D.Z.); (B.Y.)
| | - Hua-Ji Qiu
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China; (M.Y.); (M.L.); (D.P.); (Y.W.); (S.L.)
| | - Lian-Feng Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China; (M.Y.); (M.L.); (D.P.); (Y.W.); (S.L.)
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Jinzhong 030801, China; (D.Z.); (B.Y.)
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19
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Campbell A, Bae J, Hein M, Hillis SL, Rebeck ON, Rakel BA, Grice E, Gardner SE. The heterogeneous wound microbiome varies with wound care pain, dressing type, and inflammatory gene expression. Wound Repair Regen 2024; 32:811-825. [PMID: 38666460 PMCID: PMC11511792 DOI: 10.1111/wrr.13184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 03/11/2024] [Accepted: 04/04/2024] [Indexed: 09/28/2024]
Abstract
Wound dressing changes are essential procedures for wound management. However, ~50% of patients experience severe pain during these procedures despite the availability of analgesic medications, indicating a need for novel therapeutics that address underlying causes of pain. Along with other clinical factors, wound pathogens and inflammatory immune responses have previously been implicated in wound pain. To test whether these factors could contribute to severe pain during wound dressing changes, we conducted an exploratory, cross-sectional analysis of patient-reported pain, inflammatory immune responses, and wound microbiome composition in 445 wounds at the time of a study dressing change. We profiled the bacterial composition of 406 wounds using 16S ribosomal RNA amplicon sequencing and quantified gene expression of 13 inflammatory markers in wound fluid using quantitative real-time polymerase chain reaction (qPCR). Neither inflammatory gene expression nor clinically observed inflammation were associated with severe pain, but Corynebacterium and Streptococcus were of lower relative abundance in wounds of patients reporting severe pain than those reporting little or no pain. Wound microbiome composition differed by wound location, and correlated with six of the inflammatory markers, including complement receptor C5AR1, pro-inflammatory cytokine interleukin (IL)1β, chemokine IL-8, matrix metalloproteinase MMP2, and the antimicrobial peptide encoding cathelicidin antimicrobial peptide. Interestingly, we found a relationship between the wound microbiome and vacuum-assisted wound closure (VAC). These findings identify preliminary, associative relationships between wound microbiota and host factors which motivate future investigation into the directional relationships between wound care pain, wound closure technologies, and the wound microbiome.
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Affiliation(s)
- Amy Campbell
- The University of Iowa College of NursingIowa CityIowaUSA
| | - Jaewon Bae
- The University of Iowa College of NursingIowa CityIowaUSA
| | - Maria Hein
- The University of Iowa College of NursingIowa CityIowaUSA
| | | | | | | | | | - Sue E. Gardner
- The University of Iowa College of NursingIowa CityIowaUSA
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20
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Augière C, Campolina-Silva G, Vijayakumaran A, Medagedara O, Lavoie-Ouellet C, Joly Beauparlant C, Droit A, Barrachina F, Ottino K, Battistone MA, Narayan K, Hess R, Mennella V, Belleannée C. ARL13B controls male reproductive tract physiology through primary and Motile Cilia. Commun Biol 2024; 7:1318. [PMID: 39397107 PMCID: PMC11471856 DOI: 10.1038/s42003-024-07030-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 10/07/2024] [Indexed: 10/15/2024] Open
Abstract
ARL13B is a small regulatory GTPase that controls ciliary membrane composition in both motile cilia and non-motile primary cilia. In this study, we investigated the role of ARL13B in the efferent ductules, tubules of the male reproductive tract essential to male fertility in which primary and motile cilia co-exist. We used a genetically engineered mouse model to delete Arl13b in efferent ductule epithelial cells, resulting in compromised primary and motile cilia architecture and functions. This deletion led to disturbances in reabsorptive/secretory processes and triggered an inflammatory response. The observed male reproductive phenotype showed significant variability linked to partial infertility, highlighting the importance of ARL13B in maintaining a proper physiological balance in these small ducts. These results emphasize the dual role of both motile and primary cilia functions in regulating efferent duct homeostasis, offering deeper insights into how cilia related diseases affect the male reproductive system.
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Affiliation(s)
- Céline Augière
- CHU de Québec Research Center (CHUL)- Université Laval, Quebec City, QC, Canada.
- Centre de recherche en Reproduction, Développement et Santé Intergénérationnelle, Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Université Laval, Quebec City, QC, Canada.
| | - Gabriel Campolina-Silva
- CHU de Québec Research Center (CHUL)- Université Laval, Quebec City, QC, Canada
- Centre de recherche en Reproduction, Développement et Santé Intergénérationnelle, Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
| | - Aaran Vijayakumaran
- Medical Research Council Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, UK
| | - Odara Medagedara
- Medical Research Council Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, UK
| | - Camille Lavoie-Ouellet
- CHU de Québec Research Center (CHUL)- Université Laval, Quebec City, QC, Canada
- Centre de recherche en Reproduction, Développement et Santé Intergénérationnelle, Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
| | | | - Arnaud Droit
- CHU de Québec Research Center (CHUL)- Université Laval, Quebec City, QC, Canada
| | - Ferran Barrachina
- Program in Membrane Biology, Nephrology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, MA, USA
| | - Kiera Ottino
- Program in Membrane Biology, Nephrology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, MA, USA
| | - Maria Agustina Battistone
- Program in Membrane Biology, Nephrology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, MA, USA
| | - Kedar Narayan
- Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Rex Hess
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, Illinois, IL, USA
| | - Vito Mennella
- Medical Research Council Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, UK
- Department of Pathology, 10 Tennis Court Road, University of Cambridge, Cambridge, UK
| | - Clémence Belleannée
- CHU de Québec Research Center (CHUL)- Université Laval, Quebec City, QC, Canada.
- Centre de recherche en Reproduction, Développement et Santé Intergénérationnelle, Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Université Laval, Quebec City, QC, Canada.
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21
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Zhan J, Jarrell ZR, Hu X, Weinberg J, Orr M, Marts L, Jones DP, Go Y. A pilot metabolomics study across the continuum of interstitial lung disease fibrosis severity. Physiol Rep 2024; 12:e70093. [PMID: 39424430 PMCID: PMC11489002 DOI: 10.14814/phy2.70093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/08/2024] [Accepted: 10/08/2024] [Indexed: 10/21/2024] Open
Abstract
Interstitial lung diseases (ILDs) include a variety of inflammatory and fibrotic pulmonary conditions. This study employs high-resolution metabolomics (HRM) to explore plasma metabolites and pathways across ILD phenotypes, including non-fibrotic ILD, idiopathic pulmonary fibrosis (IPF), and non-IPF fibrotic ILD. The study used 80 plasma samples for HRM, and involved linear trend and group-wise analyses of metabolites altered in ILD phenotypes. We utilized limma one-way ANOVA and mummichog algorithms to identify differences in metabolites and pathways across ILD groups. Then, we focused on metabolites within critical pathways, indicated by high pathway overlap sizes and low p-values, for further analysis. Targeted HRM identified putrescine, hydroxyproline, prolyl-hydroxyproline, aspartate, and glutamate with significant linear increases in more fibrotic ILD phenotypes, suggesting their role in ILD fibrogenesis. Untargeted HRM highlighted pathway alterations in lysine, vitamin D3, tyrosine, and urea cycle metabolism, all associated with pulmonary fibrosis. In addition, methylparaben level had a significantly increasing linear trend and was higher in the IPF than fibrotic and non-ILD groups. This study highlights the importance of specific amino acids, metabolic pathways, and xenobiotics in the progression of pulmonary fibrosis.
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Affiliation(s)
- Jiada Zhan
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
- Nutrition and Health Sciences, Laney Graduate SchoolEmory UniversityAtlantaGeorgiaUSA
| | - Zachery R. Jarrell
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
| | - Xin Hu
- Gangarosa Department of Environmental Health, Rollins School of Public HealthEmory UniversityAtlantaGeorgiaUSA
| | - Jaclyn Weinberg
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
| | - Michael Orr
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
| | - Lucian Marts
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
| | - Dean P. Jones
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
- Nutrition and Health Sciences, Laney Graduate SchoolEmory UniversityAtlantaGeorgiaUSA
| | - Young‐Mi Go
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of MedicineEmory UniversityAtlantaGeorgiaUSA
- Nutrition and Health Sciences, Laney Graduate SchoolEmory UniversityAtlantaGeorgiaUSA
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22
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Guo Y, Liu J, Du X, Qi M, She T, Xue K, Wu X, Xu L, Peng B, Zhang Y, Liu Y, Jiang Z, Li X, Yuan Y. ROS exhaustion reverses the effects of hyperbaric oxygen on hemorrhagic transformation through reactivating microglia in post-stroke hyperglycemic mice. Sci Rep 2024; 14:21410. [PMID: 39271781 PMCID: PMC11399301 DOI: 10.1038/s41598-024-72454-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024] Open
Abstract
Acute ischemic stroke (AIS) is a major global health concern due to its high mortality and disability rates. Hemorrhagic transformation, a common complication of AIS, leads to poor prognosis yet lacks effective treatments. Preclinical studies indicate that hyperbaric oxygen (HBO) treatment within 12 h of AIS onset alleviates ischemia/reperfusion injuries, including hemorrhagic transformation. However, clinical trials have yielded conflicting results, suggesting some underlying mechanisms remain unclear. In this study, we confirmed that HBO treatments beginning within 1 h post reperfusion significantly alleviated the haemorrhage and neurological deficits in hyperglycemic transient middle cerebral arterial occlusion (tMCAO) mice, partly due to the inhibition of the NLRP3 inflammasome-mediated pro-inflammatory response in microglia. Notably, reactive oxygen species (ROS) mediate the anti-inflammatory and protective effect of early HBO treatment, as edaravone and N-Acetyl-L-Cysteine (NAC), two commonly used antioxidants, reversed the suppressive effect of HBO treatment on NLRP3 inflammasome-mediated inflammation in microglia. Furthermore, NAC countered the protective effect of early HBO treatment in tMCAO mice with hyperglycemia. These findings support that early HBO treatment is a promising intervention for AIS, however, caution is warranted when combining antioxidants with HBO treatment. Further assessments are needed to clarify the role of antioxidants in HBO therapy for AIS.
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Affiliation(s)
- Yanan Guo
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Jiayi Liu
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
- Jiang'an Health Institute of Rugao Municipal Health Commission, Nantong, 226534, China
| | - Xingyue Du
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Mian Qi
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Tongping She
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Ke Xue
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Xinhe Wu
- The Second People's Hospital of Nantong, Nantong, 226002, China
| | - Lihua Xu
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Bin Peng
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Yunfeng Zhang
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Yufeng Liu
- The Second People's Hospital of Nantong, Nantong, 226002, China
| | - Zhenglin Jiang
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Xia Li
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China.
| | - Yuan Yuan
- Institute of Special Environmental Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China.
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23
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Kuypers DRJ, Kamphorst JJ, de Loor H, O'Day EM. Perspective: metabolomics has the potential to change the landscape of kidney transplantation diagnostics. Biomark Med 2024; 18:787-794. [PMID: 39234983 PMCID: PMC11457662 DOI: 10.1080/17520363.2024.2394383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 08/06/2024] [Indexed: 09/06/2024] Open
Abstract
Kidney transplantation is the most efficient renal replacement therapy. Current diagnostics for monitoring graft health are either invasive or lack precision. Metabolomics is an emerging discipline focused on the analysis of the small molecules involved in metabolism. Given the kidneys' central role in metabolic homeostasis and previous observations of altered metabolites correlating with restricted kidney graft function, metabolomics is highly promising for the discovery of novel biomarkers and the development of novel diagnostics. In this perspective, we summarize the known metabolic roles for the kidney, discuss biomarkers of graft health and immune status emerging from metabolomics research, and provide our perspective on how these and future findings can be integrated in clinical practice to enable precision diagnostics.
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Affiliation(s)
- Dirk R J Kuypers
- Department of Nephrology & Renal Transplantation, University Hospitals Leuven, Belgium
- Department of Microbiology, Immunology & Transplantation, Nephrology & Renal Transplantation Research Group, KU Leuven, Belgium
| | | | - Henriette de Loor
- Department of Nephrology & Renal Transplantation, University Hospitals Leuven, Belgium
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24
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Rajaiah R, Pandey K, Acharya A, Ambikan A, Kumar N, Guda R, Avedissian SN, Montaner LJ, Cohen SM, Neogi U, Byrareddy SN. Differential immunometabolic responses to Delta and Omicron SARS-CoV-2 variants in golden syrian hamsters. iScience 2024; 27:110501. [PMID: 39171289 PMCID: PMC11338146 DOI: 10.1016/j.isci.2024.110501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 02/07/2024] [Accepted: 07/10/2024] [Indexed: 08/23/2024] Open
Abstract
Delta (B.1.617.2) and Omicron (B.1.1.529) variants of SARS-CoV-2 represents unique clinical characteristics. However, their role in altering immunometabolic regulations during acute infection remains convoluted. Here, we evaluated the differential immunopathogenesis of Delta vs. Omicron variants in Golden Syrian hamsters (GSH). The Delta variant resulted in higher virus titers in throat swabs and the lungs and exhibited higher lung damage with immune cell infiltration than the Omicron variant. The gene expression levels of immune mediators and metabolic enzymes, Arg-1 and IDO1 in the Delta-infected lungs were significantly higher compared to Omicron. Further, Delta/Omicron infection perturbed carbohydrates, amino acids, nucleotides, and TCA cycle metabolites and was differentially regulated compared to uninfected lungs. Collectively, our data provide a novel insight into immunometabolic/pathogenic outcomes for Delta vs. Omicron infection in the GSH displaying concordance with COVID-19 patients associated with inflammation and tissue injury during acute infection that offered possible new targets to develop potential therapeutics.
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Affiliation(s)
- Rajesh Rajaiah
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kabita Pandey
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Anoop Ambikan
- The Systems Virology Lab, Department of Laboratory Medicine, Division of Clinical Microbiology, ANA Futura, Karolinska Institutet, 141 52 Stockholm, Sweden
| | - Narendra Kumar
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Reema Guda
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sean N. Avedissian
- Antiviral Pharmacology Laboratory, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Luis J. Montaner
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Samuel M. Cohen
- Havlik Wall Professor of Oncology, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ujjwal Neogi
- The Systems Virology Lab, Department of Laboratory Medicine, Division of Clinical Microbiology, ANA Futura, Karolinska Institutet, 141 52 Stockholm, Sweden
| | - Siddappa N. Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
- Havlik Wall Professor of Oncology, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
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25
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Schughart K, Smith AM, Tsalik EL, Threlkeld SC, Sellers S, Fischer WA, Schreiber J, Lücke E, Cornberg M, Debarry J, Woods CW, McClain MT, Heise M. Host response to influenza infections in human blood: association of influenza severity with host genetics and transcriptomic response. Front Immunol 2024; 15:1385362. [PMID: 39192977 PMCID: PMC11347429 DOI: 10.3389/fimmu.2024.1385362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024] Open
Abstract
Introduction Influenza virus infections are a major global health problem. Influenza can result in mild/moderate disease or progress to more severe disease, leading to high morbidity and mortality. Severity is thought to be primarily driven by immunopathology, but predicting which individuals are at a higher risk of being hospitalized warrants investigation into host genetics and the molecular signatures of the host response during influenza infections. Methods Here, we performed transcriptome and genotype analysis in healthy controls and patients exhibiting mild/moderate or severe influenza (ICU patients). A unique aspect of our study was the genotyping of all participants, which allowed us to assign ethnicities based on genetic variation and assess whether the variation was correlated with expression levels. Results We identified 169 differentially expressed genes and related molecular pathways between patients in the ICU and those who were not in the ICU. The transcriptome/genotype association analysis identified 871 genes associated to a genetic variant and 39 genes distinct between African-Americans and Caucasians. We also investigated the effects of age and sex and found only a few discernible gene effects in our cohort. Discussion Together, our results highlight select risk factors that may contribute to an increased risk of ICU admission for influenza-infected patients. This should help to develop better diagnostic tools based on molecular signatures, in addition to a better understanding of the biological processes in the host response to influenza.
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Affiliation(s)
- Klaus Schughart
- Institute of Virology Münster, University of Münster, Münster, Germany
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Amber M. Smith
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Ephraim L. Tsalik
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | | | - Subhashini Sellers
- Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - William A. Fischer
- Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jens Schreiber
- Clinic of Pneumology, Otto-von-Guerike University, Magdeburg, Germany
| | - Eva Lücke
- Clinic of Pneumology, Otto-von-Guerike University, Magdeburg, Germany
| | - Markus Cornberg
- Centre for Individualised Infection Medicine (CiiM), a Joint Initiative of the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
- German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
- TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Jennifer Debarry
- Centre for Individualised Infection Medicine (CiiM), a Joint Initiative of the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Christopher W. Woods
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
- Center for Infectious Disease Diagnostics and Innovation, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Micah T. McClain
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
- Center for Infectious Disease Diagnostics and Innovation, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Mark Heise
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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26
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Lu H, Suo Z, Lin J, Cong Y, Liu Z. Monocyte-macrophages modulate intestinal homeostasis in inflammatory bowel disease. Biomark Res 2024; 12:76. [PMID: 39095853 PMCID: PMC11295551 DOI: 10.1186/s40364-024-00612-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 07/04/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Monocytes and macrophages play an indispensable role in maintaining intestinal homeostasis and modulating mucosal immune responses in inflammatory bowel disease (IBD). Although numerous studies have described macrophage properties in IBD, the underlying mechanisms whereby the monocyte-macrophage lineage modulates intestinal homeostasis during gut inflammation remain elusive. MAIN BODY In this review, we decipher the cellular and molecular mechanisms governing the generation of intestinal mucosal macrophages and fill the knowledge gap in understanding the origin, maturation, classification, and functions of mucosal macrophages in intestinal niches, particularly the phagocytosis and bactericidal effects involved in the elimination of cell debris and pathogens. We delineate macrophage-mediated immunoregulation in the context of producing pro-inflammatory and anti-inflammatory cytokines, chemokines, toxic mediators, and macrophage extracellular traps (METs), and participating in the modulation of epithelial cell proliferation, angiogenesis, and fibrosis in the intestine and its accessory tissues. Moreover, we emphasize that the maturation of intestinal macrophages is arrested at immature stage during IBD, and the deficiency of MCPIP1 involves in the process via ATF3-AP1S2 signature. In addition, we confirmed the origin potential of IL-1B+ macrophages and defined C1QB+ macrophages as mature macrophages. The interaction crosstalk between the intestine and the mesentery has been described in this review, and the expression of mesentery-derived SAA2 is upregulated during IBD, which contributes to immunoregulation of macrophage. Moreover, we also highlight IBD-related susceptibility genes (e.g., RUNX3, IL21R, GTF2I, and LILRB3) associated with the maturation and functions of macrophage, which provide promising therapeutic opportunities for treating human IBD. CONCLUSION In summary, this review provides a comprehensive, comprehensive, in-depth and novel description of the characteristics and functions of macrophages in IBD, and highlights the important role of macrophages in the molecular and cellular process during IBD.
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Affiliation(s)
- Huiying Lu
- Department of Gastroenterology, Huaihe Hospital of Henan University, Henan Province, Kaifeng, 475000, China
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China
| | - Zhimin Suo
- Department of Gastroenterology, Huaihe Hospital of Henan University, Henan Province, Kaifeng, 475000, China
| | - Jian Lin
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China
| | - Yingzi Cong
- Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Center for Human Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Zhanju Liu
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China.
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Kumar V N, Tamilanban T. Computational therapeutic repurposing of tavaborole targeting arginase-1 for venous leg ulcer. Comput Biol Chem 2024; 111:108112. [PMID: 38843583 DOI: 10.1016/j.compbiolchem.2024.108112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/19/2024]
Abstract
Venous leg ulcers (VLUs) pose a growing healthcare challenge due to aging, obesity, and sedentary lifestyles. Despite various treatments available, addressing the complex nature of VLUs remains difficult. In this context, this study investigates repurposing boronated drugs to inhibit arginase 1 activity for VLU treatment. The molecular docking study conducted by Schrodinger GLIDE targeted the binuclear manganese cluster of arginase 1 enzyme (2PHO). Further, the ligand-protein complex was subjected to molecular dynamic studies at 500 ns in Gromacs-2019.4. Trajectory analysis was performed using the GROMACS simulation package of protein RMSD, RMSF, RG, SASA, and H-Bond. The docking study revealed intriguing results where the tavaborole showed a better docking score (-3.957 Kcal/mol) compared to the substrate L-arginine (-3.379 Kcal/mol) and standard L-norvaline (-3.141 Kcal/mol). Tavaborole interaction with aspartic acid ultimately suggests that the drug molecule binds to the catalytic site of arginase 1, potentially influencing the enzyme's function. The dynamics study revealed the compounds' stability and compactness of the protein throughout the simulation. The RMSD, RMSF, SASA, RG, inter and intra H-bond, PCA, FEL, and MMBSA studies affirmed the ligand-protein and protein complex flexibility, compactness, binding energy, van der waals energy, and solvation dynamics. These results revealed the stability and the interaction of the ligand with the catalytic site of arginase 1 enzyme, triggering the study towards the VLU treatment.
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Affiliation(s)
- Naveen Kumar V
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu - 603 203, India
| | - T Tamilanban
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu - 603 203, India.
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28
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Lv J, Wang Z, Wang B, Deng C, Wang W, Sun L. S100A9 Induces Macrophage M2 Polarization and Immunomodulatory Role in the Lesion Site After Spinal Cord Injury in Rats. Mol Neurobiol 2024; 61:5525-5540. [PMID: 38206470 DOI: 10.1007/s12035-024-03920-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 01/01/2024] [Indexed: 01/12/2024]
Abstract
Immune response is pivotal in the secondary injury of spinal cord injury (SCI). Polarization of macrophages (MΦ) influences the immune response in the secondary injury, which is regulated by several immune-related proteins. M2Φ plays the immunomodulatory role in the central nervous system. This study used bioinformatic analysis and machine algorithms to screen hub immune-related proteins after SCI and experimentally investigate the role of the target protein in the M2Φ polarization and immunomodulation in rats and in vitro after SCI. We downloaded GSE151371 and GSE45006, hub immune-related genes were screened using machine learning algorithms, and the expression of S100A9 was verified by datasets. Allen's weight-drop injury SCI model in Sprague-Dawley rat and bone marrow-derived rat MΦ with myelin debris model were used to study the effects of S100A9 on M2Φ polarization and immunomodulation at the lesion site and in vitro. Bioinformatic analysis showed that S100A9 acts as a hub immune-related gene in the SCI patients and rats. S100A9 increased at the lesion site in SCI rats, and its inhibition reduced CD206 and ARG-1 expression. Exogenous S100A9 promoted CD206 and ARG-1 expression in MΦ. S100A9 also increased the expression of PD-L1 and decreased MHC II at the lesion site in SCI rats and MΦ with myelin debris, and enhanced mitochondrial activity in rat MΦ with myelin debris. In conclusion, S100A9 is an indispensable factor in the immune process in secondary injury following SCI.
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Affiliation(s)
- Junqiao Lv
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Zhiqiang Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Beiyang Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Chen Deng
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Wei Wang
- Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Lin Sun
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China.
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29
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Yadav P, Ortega JG, Tamaki W, Chien C, Chang KC, Biswas N, Pan S, Nilsson J, Yin X, Bhattacharyya A, Boostanpour K, Jujaray T, Wang J, Tsukui T, Sheppard D, Li B, Maishan M, Taenaka H, Matthay MA, Muramatsu R, Maliskova L, Ghosh A, Eckalbar WL, Molofsky AB, Wolters PJ, Tamaki SJ, Bivona T, Abate AR, Wagner A, Tharp KM, Bhattacharya M. Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.09.06.556606. [PMID: 39211079 PMCID: PMC11360891 DOI: 10.1101/2023.09.06.556606] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Monocyte-derived macrophages recruited to injured tissues induce a maladaptive fibrotic response characterized by excessive production of collagen by local fibroblasts. Macrophages initiate this programming via paracrine factors, but it is unknown whether reciprocal responses from fibroblasts enhance profibrotic polarization of macrophages. We identify macrophage-fibroblast crosstalk necessary for injury-associated fibrosis, in which macrophages induced interleukin 6 ( IL-6 ) expression in fibroblasts via purinergic receptor P2rx4 signaling, and IL-6, in turn, induced arginase 1 ( Arg1 ) expression in macrophages. Arg1 contributed to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts used as a substrate to synthesize proline, a uniquely abundant constituent of collagen. Imaging of idiopathic pulmonary fibrosis (IPF) lung samples confirmed expression of ARG1 in myeloid cells, and arginase inhibition suppressed collagen expression in cultured precision-cut IPF lung slices. Taken together, we define a circuit between macrophages and fibroblasts that facilitates cross-feeding metabolism necessary for injury-associated fibrosis.
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30
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Halasa M, Uosef A, Ubelaker HV, Subuddhi A, Mysore KR, Kubiak JZ, Ghobrial RM, Wosik J, Kloc M. Gadolinium retention effect on macrophages - a potential cause of MRI contrast agent Dotarem toxicity. Cell Tissue Res 2024; 397:51-60. [PMID: 38625373 DOI: 10.1007/s00441-024-03885-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 03/04/2024] [Indexed: 04/17/2024]
Abstract
Gadolinium is a component of the MRI contrast agent Dotarem. Although Dotarem is the least toxic among MRI contrasts used, gadolinium present in Dotarem accumulates for many years in various organs and tissues exerting toxic effects. We showed previously that gadolinium remains in macrophages for at least 7 days after exposure to Dotarem. However, very little is known about the effect of gadolinium retention on the immune cells such as macrophages. We studied the effect of 1-day and 7-day retention of gadolinium on various functions and molecular pathways of macrophages. Gadolinium retention for 7 days decreased macrophage adhesion and motility and dysregulated the expression of adhesion and fibrotic pathway-related proteins such as Notch1 and its ligand Jagged1, adhesion/migration-related proteins PAK1 and Shp1, immune response-related transcription factors Smad3 and TCF19, and chemokines CXCL10 and CXCL13, and dysregulated the mRNA expression of fibrosis-related genes involved in extracellular matrix (ECM) synthesis, such as Col6a1, Fibronectin, MMP9, and MMP12. It also completely (below a level of detection) shut down the transcription of anti-inflammatory M2 macrophage polarization marker the Arg-1. Such changes, if they occur in MRI patients, can be potentially detrimental to the patient's immune system and immune response-related processes.
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Affiliation(s)
- Marta Halasa
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA
- Department of Surgery, The Houston Methodist Hospital, 6670 Bertner Ave., Houston, TX, 77030, USA
| | - Ahmed Uosef
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA
- Department of Surgery, The Houston Methodist Hospital, 6670 Bertner Ave., Houston, TX, 77030, USA
| | - Henry V Ubelaker
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA
- Department of Surgery, The Houston Methodist Hospital, 6670 Bertner Ave., Houston, TX, 77030, USA
| | - Arijita Subuddhi
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA
- Tuberculosis Research Advancement Center (TRAC), Emory Vaccine Center, Emory National Primate Research Center, Atlanta, GA, USA
| | - Krupa R Mysore
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Jacek Z Kubiak
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute (WIM-PIB), Szaserow 128, 04-141, Warsaw, Poland
- Dynamics and Mechanics of Epithelia Group, Institute of Genetics and Development of Rennes, CNRS, UMR 6290, Faculty of Medicine, University of Rennes, 35043, Rennes, France
| | - Rafik M Ghobrial
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA
- Department of Surgery, The Houston Methodist Hospital, 6670 Bertner Ave., Houston, TX, 77030, USA
| | - Jarek Wosik
- Electrical and Computer Engineering Department, University of Houston, Houston Science Center Building, Room 324, 4302 University Drive, Houston, TX, 77204, USA.
- Texas Center for Superconductivity, University of Houston, Houston Science Center Building, Room 324, 4302 University Drive, Houston, TX, 77204, USA.
| | - Malgorzata Kloc
- Transplant Immunology, The Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX, 77030, USA.
- Department of Surgery, The Houston Methodist Hospital, 6670 Bertner Ave., Houston, TX, 77030, USA.
- MD Anderson Cancer Center, Department of Genetics, The University of Texas, Houston, TX, USA.
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31
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Xie G, Gao X, Guo Q, Liang H, Yao L, Li W, Ma B, Wu N, Han X, Li J. Cannabidiol ameliorates PTSD-like symptoms by inhibiting neuroinflammation through its action on CB2 receptors in the brain of male mice. Brain Behav Immun 2024; 119:945-964. [PMID: 38759736 DOI: 10.1016/j.bbi.2024.05.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 05/05/2024] [Accepted: 05/12/2024] [Indexed: 05/19/2024] Open
Abstract
Post-traumatic stress disorder (PTSD) is a debilitating mental health disease related to traumatic experience, and its treatment outcomes are unsatisfactory. Accumulating research has indicated that cannabidiol (CBD) exhibits anti-PTSD effects, however, the underlying mechanism of CBD remains inadequately investigated. Although many studies pertaining to PTSD have primarily focused on aberrations in neuronal functioning, the present study aimed to elucidate the involvement and functionality of microglia/macrophages in PTSD while also investigated the modulatory effects of CBD on neuroinflammation associated with this condition. We constructed a modified single-prolonged stress (SPS) mice PTSD model and verified the PTSD-related behaviors by various behavioral tests (contextual freezing test, elevated plus maze test, tail suspension test and novel object recognition test). We observed a significant upregulation of Iba-1 and alteration of microglial/macrophage morphology within the prefrontal cortex and hippocampus, but not the amygdala, two weeks after the PTSD-related stress, suggesting a persistent neuroinflammatory phenotype in the PTSD-modeled group. CBD (10 mg/kg, i.p.) inhibited all PTSD-related behaviors and reversed the alterations in both microglial/macrophage quantity and morphology when administered prior to behavioral assessments. We further found increased pro-inflammatory factors, decreased PSD95 expression, and impaired synaptic density in the hippocampus of the modeled group, all of which were also restored by CBD treatment. CBD dramatically increased the level of anandamide, one of the endocannabinoids, and cannabinoid type 2 receptors (CB2Rs) transcripts in the hippocampus compared with PTSD-modeled group. Importantly, we discovered the expression of CB2Rs mRNA in Arg-1-positive cells in vivo and found that the behavioral effects of CBD were diminished by CB2Rs antagonist AM630 (1 mg/kg, i.p.) and both the behavioral and molecular effects of CBD were abolished in CB2Rs knockout mice. These findings suggest that CBD would alleviate PTSD-like behaviors in mice by suppressing PTSD-related neuroinflammation and upregulation and activation of CB2Rs may serve as one of the underlying mechanisms for this therapeutic effect. The present study offers innovative experimental evidence supporting the utilization of CBD in PTSD treatment from the perspective of its regulation of neuroinflammation, and paves the way for leveraging the endocannabinoid system to regulate neuroinflammation as a potential therapeutic approach for psychiatric disorders.
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Affiliation(s)
- Guanbo Xie
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Xinwei Gao
- Chinese Institute for Brain Research, Beijing 102206, China
| | - Qingchun Guo
- Chinese Institute for Brain Research, Beijing 102206, China; School of Biomedical Engineering, Capital Medical University, Beijing 100069, China
| | - Haizhen Liang
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Lan Yao
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Wenjuan Li
- Chinese Institute for Brain Research, Beijing 102206, China
| | - Baiping Ma
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Ning Wu
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
| | - Xiao Han
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
| | - Jin Li
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
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32
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Kukan EN, Fabiano GL, Cobb BA. Siglecs as modulators of macrophage phenotype and function. Semin Immunol 2024; 73:101887. [PMID: 39357273 DOI: 10.1016/j.smim.2024.101887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/15/2024] [Accepted: 09/15/2024] [Indexed: 10/04/2024]
Abstract
The sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors expressed widely on cells of the hematopoietic system. Siglecs recognize terminal sialic acid residues on glycans and often initiate intracellular signaling upon ligation. Cells can express several Siglec family members concurrently with each showing differential specificities for sialic acid linkages to the underlying glycan as well as varied hydroxyl substitutions, allowing these receptors to fine tune downstream responses. Macrophages are among the many immune cells that express Siglec family members. Macrophages exhibit wide diversity in their phenotypes and functions, and this diversity is often mediated by signals from the local environment, including those from glycans. In this review, we detail the known expression of Siglecs in macrophages while focusing on their functional importance and potential clinical relevance.
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Affiliation(s)
- Emily N Kukan
- Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, United States
| | - Gabrielle L Fabiano
- Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, United States
| | - Brian A Cobb
- Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, United States.
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33
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Kim SW, Kim CW, Moon YA, Kim HS. Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment. Anim Cells Syst (Seoul) 2024; 28:123-136. [PMID: 38577621 PMCID: PMC10993762 DOI: 10.1080/19768354.2024.2336249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/17/2024] [Indexed: 04/06/2024] Open
Abstract
The tumor microenvironment comprises both tumor and non-tumor stromal cells, including tumor-associated macrophages (TAMs), endothelial cells, and carcinoma-associated fibroblasts. TAMs, major components of non-tumor stromal cells, play a crucial role in creating an immunosuppressive environment by releasing cytokines, chemokines, growth factors, and immune checkpoint proteins that inhibit T cell activity. During tumors develop, cancer cells release various mediators, including chemokines and metabolites, that recruit monocytes to infiltrate tumor tissues and subsequently induce an M2-like phenotype and tumor-promoting properties. Metabolites are often overlooked as metabolic waste or detoxification products but may contribute to TAM polarization. Furthermore, macrophages display a high degree of plasticity among immune cells in the tumor microenvironment, enabling them to either inhibit or facilitate cancer progression. Therefore, TAM-targeting has emerged as a promising strategy in tumor immunotherapy. This review provides an overview of multiple representative metabolites involved in TAM phenotypes, focusing on their role in pro-tumoral polarization of M2.
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Affiliation(s)
- Seung Woo Kim
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Chan Woo Kim
- Cancer Immunotherapy Evaluation Team, Non-Clinical Evaluation Center, Osong Medical Innovation Foundation (KBIO Health), Cheongju, Republic of Korea
| | - Young-Ah Moon
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Hong Seok Kim
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
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34
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Kobayashi T, Sakamoto A, Hisano T, Kashiwagi K, Igarashi K, Takao K, Uemura T, Furuchi T, Sugita Y, Moriya T, Oshima T, Terui Y. Caldomycin, a new guanidopolyamine produced by a novel agmatine homocoupling enzyme involved in homospermidine biosynthesis. Sci Rep 2024; 14:7566. [PMID: 38555406 PMCID: PMC10981699 DOI: 10.1038/s41598-024-58296-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/27/2024] [Indexed: 04/02/2024] Open
Abstract
An extreme thermophilic bacterium, Thermus thermophilus produces more than 20 unusual polyamines, but their biosynthetic pathways, including homospermidine, are not yet fully understood. Two types of homospermidine synthases have been identified in plants and bacteria, which use spermidine and putrescine or two molecules of putrescine as substrates. However, homospermidine synthases with such substrate specificity have not been identified in T. thermophilus. Here we identified a novel agmatine homocoupling enzyme that is involved in homospermidine biosynthesis in T. thermophilus. The reaction mechanism is different from that of a previously described homospermidine synthase, and involves conjugation of two molecules of agmatine, which produces a diamidino derivative of homospermidine (caldomycin) as an immediate precursor of homospermidine. We conclude that there is a homospermidine biosynthetic pathway from agmatine via caldomycin synthase followed by ureohydrolase in T. thermophilus. Furthermore, it is shown that caldomycin is a novel compound existing in nature.
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Affiliation(s)
- Teruyuki Kobayashi
- Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba, 288-0025, Japan
| | - Akihiko Sakamoto
- Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba, 288-0025, Japan
- Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa, Tokyo, Japan
| | - Tamao Hisano
- RIKEN Center for Biosystems Dynamics Research (BDR), Tsurumi, Kanagawa, Japan
| | - Keiko Kashiwagi
- Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba, 288-0025, Japan
| | - Kazuei Igarashi
- Amine Pharma Research Institute, Innovation Plaza at Chiba University, Chiba, Japan
| | - Koichi Takao
- Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan
| | - Takeshi Uemura
- Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan
| | - Takemitsu Furuchi
- Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan
| | - Yoshiaki Sugita
- Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan
| | - Toshiyuki Moriya
- Institute of Environmental Biology, Kyowa-Kako, Machida, Tokyo, Japan
| | - Tairo Oshima
- Institute of Environmental Biology, Kyowa-Kako, Machida, Tokyo, Japan
| | - Yusuke Terui
- Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba, 288-0025, Japan.
- School of Pharmacy, International University of Health and Welfare, Otawara, Tochigi, Japan.
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35
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Lozinski BM, Ghorbani S, Yong VW. Biology of neurofibrosis with focus on multiple sclerosis. Front Immunol 2024; 15:1370107. [PMID: 38596673 PMCID: PMC11002094 DOI: 10.3389/fimmu.2024.1370107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/12/2024] [Indexed: 04/11/2024] Open
Abstract
Tissue damage elicits a wound healing response of inflammation and remodeling aimed at restoring homeostasis. Dysregulation of wound healing leads to accumulation of effector cells and extracellular matrix (ECM) components, collectively termed fibrosis, which impairs organ functions. Fibrosis of the central nervous system, neurofibrosis, is a major contributor to the lack of neural regeneration and it involves fibroblasts, microglia/macrophages and astrocytes, and their deposited ECM. Neurofibrosis occurs commonly across neurological conditions. This review describes processes of wound healing and fibrosis in tissues in general, and in multiple sclerosis in particular, and considers approaches to ameliorate neurofibrosis to enhance neural recovery.
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Affiliation(s)
| | | | - V. Wee Yong
- Hotchkiss Brain Institute and the Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada
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36
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Hoque MM, Gbadegoye JO, Hassan FO, Raafat A, Lebeche D. Cardiac fibrogenesis: an immuno-metabolic perspective. Front Physiol 2024; 15:1336551. [PMID: 38577624 PMCID: PMC10993884 DOI: 10.3389/fphys.2024.1336551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 03/07/2024] [Indexed: 04/06/2024] Open
Abstract
Cardiac fibrosis is a major and complex pathophysiological process that ultimately culminates in cardiac dysfunction and heart failure. This phenomenon includes not only the replacement of the damaged tissue by a fibrotic scar produced by activated fibroblasts/myofibroblasts but also a spatiotemporal alteration of the structural, biochemical, and biomechanical parameters in the ventricular wall, eliciting a reactive remodeling process. Though mechanical stress, post-infarct homeostatic imbalances, and neurohormonal activation are classically attributed to cardiac fibrosis, emerging evidence that supports the roles of immune system modulation, inflammation, and metabolic dysregulation in the initiation and progression of cardiac fibrogenesis has been reported. Adaptive changes, immune cell phenoconversions, and metabolic shifts in the cardiac nonmyocyte population provide initial protection, but persistent altered metabolic demand eventually contributes to adverse remodeling of the heart. Altered energy metabolism, mitochondrial dysfunction, various immune cells, immune mediators, and cross-talks between the immune cells and cardiomyocytes play crucial roles in orchestrating the transdifferentiation of fibroblasts and ensuing fibrotic remodeling of the heart. Manipulation of the metabolic plasticity, fibroblast-myofibroblast transition, and modulation of the immune response may hold promise for favorably modulating the fibrotic response following different cardiovascular pathological processes. Although the immunologic and metabolic perspectives of fibrosis in the heart are being reported in the literature, they lack a comprehensive sketch bridging these two arenas and illustrating the synchrony between them. This review aims to provide a comprehensive overview of the intricate relationship between different cardiac immune cells and metabolic pathways as well as summarizes the current understanding of the involvement of immune-metabolic pathways in cardiac fibrosis and attempts to identify some of the previously unaddressed questions that require further investigation. Moreover, the potential therapeutic strategies and emerging pharmacological interventions, including immune and metabolic modulators, that show promise in preventing or attenuating cardiac fibrosis and restoring cardiac function will be discussed.
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Affiliation(s)
- Md Monirul Hoque
- Departments of Physiology, The University of Tennessee Health Science Center, Memphis, TN, United States
- College of Graduate Health Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Joy Olaoluwa Gbadegoye
- Departments of Physiology, The University of Tennessee Health Science Center, Memphis, TN, United States
- College of Graduate Health Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Fasilat Oluwakemi Hassan
- Departments of Physiology, The University of Tennessee Health Science Center, Memphis, TN, United States
- College of Graduate Health Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Amr Raafat
- Departments of Physiology, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Djamel Lebeche
- Departments of Physiology, The University of Tennessee Health Science Center, Memphis, TN, United States
- College of Graduate Health Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States
- Medicine-Cardiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
- Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, United States
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37
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Hashemi Z, Hui T, Wu A, Matouba D, Zukowski S, Nejati S, Lim C, Bruzzese J, Seabold K, Mills C, Lin C, Wrath K, Wang H, Wang H, Verzi MP, Perekatt A. Smad4 Loss in the Mouse Intestinal Epithelium Alleviates the Pathological Fibrotic Response to Injury in the Colon. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.08.578000. [PMID: 38559102 PMCID: PMC10979917 DOI: 10.1101/2024.03.08.578000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel diseases (IBDs). Unresolved injury and inflammation, on the other hand, increases pathological fibrosis and the predisposition to cancer. Loss of Smad4, a tumor suppressor, is known to increase colitis-associated cancer in mouse models of chronic IBD. Since common biological processes are involved in both injury repair and tumor growth, we sought to investigate the effect of Smad4 loss on the response to epithelial injury. To this end, Smad4 was knocked out specifically in the intestinal epithelium and transcriptomic and morphological changes compared between wild type mice and Smad4 knock out mice after DSS-induced injury. We find that Smad4 loss alleviates pathological fibrosis and enhances mucosal repair. The transcriptomic changes specific to epithelium indicate molecular changes that affect epithelial extracellular matrix (ECM) and promote enhanced mucosal repair. These findings suggest that the biological processes that promote wound healing alleviate the pathological fibrotic response to DSS. Therefore, these mucosal repair processes could be exploited to develop therapies that promote normal wound healing and prevent fibrosis. NEW AND NOTEWORTHY We show that transcriptomic changes due to Smad4 loss in the colonic epithelium alleviates the pathological fibrotic response to DSS in an IBD mouse model of acute inflammation. Most notably, we find that collagen deposition in the epithelial ECM, as opposed to that in the lamina propria, correlates with epithelial changes that enhance wound healing. This is the first report on a mouse model providing alleviated fibrotic response in a DSS-IBD mouse model in vivo .
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Dumitru A, Matei E, Cozaru GC, Chisoi A, Alexandrescu L, Popescu RC, Butcaru MP, Dumitru E, Rugină S, Tocia C. Endotoxin Inflammatory Action on Cells by Dysregulated-Immunological-Barrier-Linked ROS-Apoptosis Mechanisms in Gut-Liver Axis. Int J Mol Sci 2024; 25:2472. [PMID: 38473721 DOI: 10.3390/ijms25052472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
Our study highlighted the immune changes by pro-inflammatory biomarkers in the gut-liver-axis-linked ROS-cell death mechanisms in chronic and acute inflammations when gut cells are exposed to endotoxins in patients with hepatic cirrhosis or steatosis. In duodenal tissue samples, gut immune barrier dysfunction was analyzed by pro-inflammatory biomarker expressions, oxidative stress, and cell death by flow cytometry methods. A significant innate and adaptative immune system reaction was observed as result of persistent endotoxin action in gut cells in chronic inflammation tissue samples recovered from hepatic cirrhosis with the A-B child stage. Instead, in patients with C child stage of HC, the endotoxin tolerance was installed in cells, characterized by T lymphocyte silent activation and increased Th1 cytokines expression. Interesting mechanisms of ROS-cell death were observed in chronic and acute inflammation samples when gut cells were exposed to endotoxins and immune changes in the gut-liver axis. Late apoptosis represents the chronic response to injury induction by the gut immune barrier dysfunction, oxidative stress, and liver-dysregulated barrier. Meanwhile, necrosis represents an acute and severe reply to endotoxin action on gut cells when the immune system reacts to pro-inflammatory Th1 and Th2 cytokines releasing, offering protection against PAMPs/DAMPs by monocytes and T lymphocyte activation. Flow cytometric analysis of pro-inflammatory biomarkers linked to oxidative stress-cell death mechanisms shown in our study recommends laboratory techniques in diagnostic fields.
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Affiliation(s)
- Andrei Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Elena Matei
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Georgeta Camelia Cozaru
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Anca Chisoi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Luana Alexandrescu
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Răzvan Cătălin Popescu
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Mihaela Pundiche Butcaru
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Eugen Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Sorin Rugină
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Cristina Tocia
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
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Flanagan T, Foster TP, Galbato TE, Lum PY, Louie B, Song G, Halberstadt AL, Billac GB, Nichols CD. Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression. ACS Pharmacol Transl Sci 2024; 7:478-492. [PMID: 38357283 PMCID: PMC10863441 DOI: 10.1021/acsptsci.3c00297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 02/16/2024]
Abstract
Functional selectivity in the context of serotonin 2A (5-HT2A) receptor agonists is often described as differences psychedelic compounds have in the activation of Gq vs β-arrestin signaling in the brain and how that may relate to inducing psychoactive and hallucinatory properties with respect to each other. However, the presence of 5-HT2A receptors throughout the body in several cell types, including endothelial, endocrine, and immune-related tissues, suggests that functional selectivity may exist in the periphery as well. Here, we examine functional selectivity between two 5-HT2A receptor agonists of the phenylalkylamine class: (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] and (R)-2,5-dimethoxy-4-trifluoromethylamphetamine [(R)-DOTFM]. Despite comparable in vitro activity at the 5-HT2A receptor as well as similar behavioral potency, (R)-DOTFM does not exhibit an ability to prevent inflammation or elevated airway hyperresponsiveness (AHR) in an acute murine ovalbumin-induced asthma model as does (R)-DOI. Furthermore, there are distinct differences between protein expression and inflammatory-related gene expression in pulmonary tissues between the two compounds. Using (R)-DOI and (R)-DOTFM as tools, we further elucidated the anti-inflammatory mechanisms underlying the powerful anti-inflammatory effects of certain psychedelics and identified key mechanistic components of the anti-inflammatory effects of psychedelics, including suppression of arginase 1 expression.
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Affiliation(s)
- Thomas
W. Flanagan
- Department
of Pharmacology and Experimental TherapeuticsLouisiana State University Health Sciences CenterNew Orleans, Louisiana70112, United States
| | - Timothy P. Foster
- Department
of Microbiology, Immunology, and ParasitologyLouisiana State University Health Sciences CenterNew Orleans, Louisiana70112, United States
| | - Thomas E. Galbato
- Department
of Microbiology, Immunology, and ParasitologyLouisiana State University Health Sciences CenterNew Orleans, Louisiana70112, United States
| | - Pek Yee Lum
- Auransa
Inc.Palo Alto, California94301, United States
| | - Brent Louie
- Auransa
Inc.Palo Alto, California94301, United States
| | - Gavin Song
- Auransa
Inc.Palo Alto, California94301, United States
| | - Adam L. Halberstadt
- Department
of PsychiatryUniversity of San Diego, California, San Diego, California92093, United States
| | - Gerald B. Billac
- Department
of Pharmacology and Experimental TherapeuticsLouisiana State University Health Sciences CenterNew Orleans, Louisiana70112, United States
| | - Charles D. Nichols
- Department
of Pharmacology and Experimental TherapeuticsLouisiana State University Health Sciences CenterNew Orleans, Louisiana70112, United States
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40
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Luo EY, Sugimura RR. Taming microglia: the promise of engineered microglia in treating neurological diseases. J Neuroinflammation 2024; 21:19. [PMID: 38212785 PMCID: PMC10785527 DOI: 10.1186/s12974-024-03015-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 01/04/2024] [Indexed: 01/13/2024] Open
Abstract
Microglia, the CNS-resident immune cells, are implicated in many neurological diseases. Nearly one in six of the world's population suffers from neurological disorders, encompassing neurodegenerative and neuroautoimmune diseases, most with dysregulated neuroinflammation involved. Activated microglia become phagocytotic and secret various immune molecules, which are mediators of the brain immune microenvironment. Given their ability to penetrate through the blood-brain barrier in the neuroinflammatory context and their close interaction with neurons and other glial cells, microglia are potential therapeutic delivery vehicles and modulators of neuronal activity. Re-engineering microglia to treat neurological diseases is, thus, increasingly gaining attention. By altering gene expression, re-programmed microglia can be utilized to deliver therapeutics to targeted sites and control neuroinflammation in various neuroinflammatory diseases. This review addresses the current development in microglial engineering, including genetic targeting and therapeutic modulation. Furthermore, we discuss limitations to the genetic engineering techniques and models used to test the functionality of re-engineered microglia, including cell culture and animal models. Finally, we will discuss future directions for the application of engineered microglia in treating neurological diseases.
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Affiliation(s)
- Echo Yongqi Luo
- School of Biological Sciences, Faculty of Science, The University of Hong Kong, Pokfulam, Hong Kong
| | - Rio Ryohichi Sugimura
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
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41
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Kapnick SM, Martin CA, Jewell CM. Engineering metabolism to modulate immunity. Adv Drug Deliv Rev 2024; 204:115122. [PMID: 37935318 PMCID: PMC10843796 DOI: 10.1016/j.addr.2023.115122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 07/19/2023] [Accepted: 10/25/2023] [Indexed: 11/09/2023]
Abstract
Metabolic programming and reprogramming have emerged as pivotal mechanisms for altering immune cell function. Thus, immunometabolism has become an attractive target area for treatment of immune-mediated disorders. Nonetheless, many hurdles to delivering metabolic cues persist. In this review, we consider how biomaterials are poised to transform manipulation of immune cell metabolism through integrated control of metabolic configurations to affect outcomes in autoimmunity, regeneration, transplant, and cancer. We emphasize the features of nanoparticles and other biomaterials that permit delivery of metabolic cues to the intracellular compartment of immune cells, or strategies for altering signals in the extracellular space. We then provide perspectives on the potential for reciprocal regulation of immunometabolism by the physical properties of materials themselves. Lastly, opportunities for clinical translation are highlighted. This discussion contributes to our understanding of immunometabolism, biomaterials-based strategies for altering metabolic configurations in immune cells, and emerging concepts in this evolving field.
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Affiliation(s)
- Senta M Kapnick
- Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, USA; Department of Veterans Affairs, VA Maryland Health Care System, 10 N Green Street, Baltimore, MD, USA
| | - Corinne A Martin
- Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, USA
| | - Christopher M Jewell
- Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, USA; Department of Veterans Affairs, VA Maryland Health Care System, 10 N Green Street, Baltimore, MD, USA; Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, MD, USA; Marlene and Stewart Greenebaum Comprehensive Cancer Center, 22 S Greene Street, Suite N9E17, Baltimore, MD, USA.
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42
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Cai Y, Xiong M, Xin Z, Liu C, Ren J, Yang X, Lei J, Li W, Liu F, Chu Q, Zhang Y, Yin J, Ye Y, Liu D, Fan Y, Sun S, Jing Y, Zhao Q, Zhao L, Che S, Zheng Y, Yan H, Ma S, Wang S, Izpisua Belmonte JC, Qu J, Zhang W, Liu GH. Decoding aging-dependent regenerative decline across tissues at single-cell resolution. Cell Stem Cell 2023; 30:1674-1691.e8. [PMID: 37898124 DOI: 10.1016/j.stem.2023.09.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 08/28/2023] [Accepted: 09/27/2023] [Indexed: 10/30/2023]
Abstract
Regeneration across tissues and organs exhibits significant variation throughout the body and undergoes a progressive decline with age. To decode the relationships between aging and regenerative capacity, we conducted a comprehensive single-cell transcriptome analysis of regeneration in eight tissues from young and aged mice. We employed diverse analytical models to study tissue regeneration and unveiled the intricate cellular and molecular mechanisms underlying the attenuated regenerative processes observed in aged tissues. Specifically, we identified compromised stem cell mobility and inadequate angiogenesis as prominent contributors to this age-associated decline in regenerative capacity. Moreover, we discovered a unique subset of Arg1+ macrophages that were activated in young tissues but suppressed in aged regenerating tissues, suggesting their important role in age-related immune response disparities during regeneration. This study provides a comprehensive single-cell resource for identifying potential targets for interventions aimed at enhancing regenerative outcomes in the aging population.
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Affiliation(s)
- Yusheng Cai
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Muzhao Xiong
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zijuan Xin
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Chengyu Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Jie Ren
- Key Laboratory of RNA Science and Engineering, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; Aging Biomarker Consortium, China
| | - Xiying Yang
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang 261053, China
| | - Jinghui Lei
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Wei Li
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Feifei Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Qun Chu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yiyuan Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Jian Yin
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yanxia Ye
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Dingyi Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yanling Fan
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China
| | - Shuhui Sun
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yaobin Jing
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Qian Zhao
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Liyun Zhao
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Shanshan Che
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yandong Zheng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Haoteng Yan
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Shuai Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Aging Biomarker Consortium, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Aging Biomarker Consortium, China
| | | | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Aging Biomarker Consortium, China.
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Aging Biomarker Consortium, China.
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Aging Biomarker Consortium, China.
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43
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Sun XR, Yao ZM, Chen L, Huang J, Dong SY. Metabolic reprogramming regulates microglial polarization and its role in cerebral ischemia reperfusion. Fundam Clin Pharmacol 2023; 37:1065-1078. [PMID: 37339781 DOI: 10.1111/fcp.12928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 05/12/2023] [Accepted: 06/07/2023] [Indexed: 06/22/2023]
Abstract
The brain is quite sensitive to changes in energy supply because of its high energetic demand. Even small changes in energy metabolism may be the basis of impaired brain function, leading to the occurrence and development of cerebral ischemia/reperfusion (I/R) injury. Abundant evidence supports that metabolic defects of brain energy during the post-reperfusion period, especially low glucose oxidative metabolism and elevated glycolysis levels, which play a crucial role in cerebral I/R pathophysiology. Whereas research on brain energy metabolism dysfunction under the background of cerebral I/R mainly focuses on neurons, the research on the complexity of microglia energy metabolism in cerebral I/R is just emerging. As resident immune cells of the central nervous system, microglia activate rapidly and then transform into an M1 or M2 phenotype to correspond to changes in brain homeostasis during cerebral I/R injury. M1 microglia release proinflammatory factors to promote neuroinflammation, while M2 microglia play a neuroprotective role by secreting anti-inflammatory factors. The abnormal brain microenvironment promotes the metabolic reprogramming of microglia, which further affects the polarization state of microglia and disrupts the dynamic equilibrium of M1/M2, resulting in the aggravation of cerebral I/R injury. Increasing evidence suggests that metabolic reprogramming is a key driver of microglial inflammation. For example, M1 microglia preferentially produce energy through glycolysis, while M2 microglia provide energy primarily through oxidative phosphorylation. In this review, we highlight the emerging significance of regulating microglial energy metabolism in cerebral I/R injury.
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Affiliation(s)
- Xiao-Rong Sun
- Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, China
| | - Zi-Meng Yao
- Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, China
| | - Lei Chen
- Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, China
| | - Jie Huang
- Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, China
| | - Shu-Ying Dong
- Department of Pharmacology, School of Pharmacy, Bengbu Medical College, Bengbu, China
- Bengbu Medical College Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu, China
- Anhui Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, China
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44
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LaCroix IS, Cralley A, Moore EE, Cendali FI, Dzieciatkowska M, Hom P, Mitra S, Cohen M, Silliman C, Sauaia A, Hansen KC, D’Alessandro A. Omics Signatures of Tissue Injury and Hemorrhagic Shock in Swine. Ann Surg 2023; 278:e1299-e1312. [PMID: 37334680 PMCID: PMC10728352 DOI: 10.1097/sla.0000000000005944] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
OBJECTIVE Advanced mass spectrometry methods were leveraged to analyze both proteomics and metabolomics signatures in plasma upon controlled tissue injury (TI) and hemorrhagic shock (HS)-isolated or combined-in a swine model, followed by correlation to viscoelastic measurements of coagulopathy via thrombelastography. BACKGROUND TI and HS cause distinct molecular changes in plasma in both animal models and trauma patients. However, the contribution to coagulopathy of trauma, the leading cause of preventable mortality in this patient population remains unclear. The recent development of a swine model for isolated or combined TI+HS facilitated the current study. METHODS Male swine (n=17) were randomized to either isolated or combined TI and HS. Coagulation status was analyzed by thrombelastography during the monitored time course. The plasma fractions of the blood draws (at baseline; end of shock; and at 30 minutes, 1, 2, and 4 hours after shock) were analyzed by mass spectrometry-based proteomics and metabolomics workflows. RESULTS HS-isolated or combined with TI-caused the most severe omic alterations during the monitored time course. While isolated TI delayed the activation of coagulation cascades. Correlation to thrombelastography parameters of clot strength (maximum amplitude) and breakdown (LY30) revealed signatures of coagulopathy which were supported by analysis of gene ontology-enriched biological pathways. CONCLUSION The current study provides a comprehensive characterization of proteomic and metabolomic alterations to combined or isolated TI and HS in a swine model and identifies early and late omics correlates to viscoelastic measurements in this system.
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Affiliation(s)
- Ian S. LaCroix
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
| | - Alexis Cralley
- Department of Surgery, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA
| | - Ernest E. Moore
- Department of Surgery, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA
- Ernest E Moore Shock Trauma Center at Denver Health, Denver, CO, USA
| | - Francesca I Cendali
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
| | - Monika Dzieciatkowska
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
| | - Patrick Hom
- Department of Surgery, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA
| | - Sanchayita Mitra
- Department of Surgery, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA
| | | | - Christopher Silliman
- Vitalant Research Institute, Denver, CO, USA
- Department of Pediatrics, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA
| | - Angela Sauaia
- Ernest E Moore Shock Trauma Center at Denver Health, Denver, CO, USA
| | - Kirk C Hansen
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
| | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
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45
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Esperante D, Gutiérrez MIM, Issa ME, Schcolnik-Cabrera A, Mendlovic F. Similarities and divergences in the metabolism of immune cells in cancer and helminthic infections. Front Oncol 2023; 13:1251355. [PMID: 38044996 PMCID: PMC10690632 DOI: 10.3389/fonc.2023.1251355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 10/16/2023] [Indexed: 12/05/2023] Open
Abstract
Energetic and nutritional requirements play a crucial role in shaping the immune cells that infiltrate tumor and parasite infection sites. The dynamic interaction between immune cells and the microenvironment, whether in the context of tumor or helminth infection, is essential for understanding the mechanisms of immunological polarization and developing strategies to manipulate them in order to promote a functional and efficient immune response that could aid in the treatment of these conditions. In this review, we present an overview of the immune response triggered during tumorigenesis and establishment of helminth infections, highlighting the transition to chronicity in both cases. We discuss the energetic demands of immune cells under normal conditions and in the presence of tumors and helminths. Additionally, we compare the metabolic changes that occur in the tumor microenvironment and the infection site, emphasizing the alterations that are induced to redirect the immune response, thereby promoting the survival of cancer cells or helminths. This emerging discipline provides valuable insights into disease pathogenesis. We also provide examples of novel strategies to enhance immune activity by targeting metabolic pathways that shape immune phenotypes, with the aim of achieving positive outcomes in cancer and helminth infections.
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Affiliation(s)
- Diego Esperante
- Plan de Estudios Combinados en Medicina (PECEM), Facultad de Medicina, Universidad Nacional Autonóma de México (UNAM), Mexico City, Mexico
| | - Mónica Itzel Martínez Gutiérrez
- Plan de Estudios Combinados en Medicina (PECEM), Facultad de Medicina, Universidad Nacional Autonóma de México (UNAM), Mexico City, Mexico
| | - Mark E. Issa
- Department of Neurology, Massachusetts General Hospital, Charlestown, MA, United States
| | - Alejandro Schcolnik-Cabrera
- Département de Biochimie et Médicine Moléculaire, Université de Montréal, Succursale Centre-Ville, Montréal, QC, Canada
- Department of Immunology-Oncology, Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC, Canada
| | - Fela Mendlovic
- Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte, Huixquilucan, Mexico
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46
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Zhu J, Liu J, Yan C, Wang D, Pan W. Trained immunity: a cutting edge approach for designing novel vaccines against parasitic diseases? Front Immunol 2023; 14:1252554. [PMID: 37868995 PMCID: PMC10587610 DOI: 10.3389/fimmu.2023.1252554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/25/2023] [Indexed: 10/24/2023] Open
Abstract
The preventive situation of parasitosis, a global public health burden especially for developing countries, is not looking that good. Similar to other infections, vaccines would be the best choice for preventing and controlling parasitic infection. However, ideal antigenic molecules for vaccine development have not been identified so far, resulting from the complicated life history and enormous genomes of the parasites. Furthermore, the suppression or down-regulation of anti-infectious immunity mediated by the parasites or their derived molecules can compromise the effect of parasitic vaccines. Comparing the early immune profiles of several parasites in the permissive and non-permissive hosts, a robust innate immune response is proposed to be a critical event to eliminate the parasites. Therefore, enhancing innate immunity may be essential for designing novel and effective parasitic vaccines. The newly emerging trained immunity (also termed innate immune memory) has been increasingly recognized to provide a novel perspective for vaccine development targeting innate immunity. This article reviews the current status of parasitic vaccines and anti-infectious immunity, as well as the conception, characteristics, and mechanisms of trained immunity and its research progress in Parasitology, highlighting the possible consideration of trained immunity in designing novel vaccines against parasitic diseases.
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Affiliation(s)
- Jinhang Zhu
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- The Second Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jiaxi Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Chao Yan
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Dahui Wang
- Liangshan College (Li Shui) China, Lishui University, Lishui, Zhejiang, China
| | - Wei Pan
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
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Maizels RM, Gause WC. Targeting helminths: The expanding world of type 2 immune effector mechanisms. J Exp Med 2023; 220:e20221381. [PMID: 37638887 PMCID: PMC10460967 DOI: 10.1084/jem.20221381] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 06/24/2023] [Accepted: 08/09/2023] [Indexed: 08/29/2023] Open
Abstract
In this new review, Rick Maizels and Bill Gause summarize how type 2 immune responses combat helminth parasites through novel mechanisms, coordinating multiple innate and adaptive cell and molecular players that can eliminate infection and repair-resultant tissue damage.
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Affiliation(s)
- Rick M. Maizels
- Wellcome Centre for Integrative Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, UK
| | - William C. Gause
- Center for Immunity and Inflammation, Rutgers Biomedical Health Sciences Institute for Infectious and Inflammatory Diseases, New Jersey Medical School, Rutgers Biomedical Health Sciences, Newark, NJ, USA
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48
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Gelbach PE, Finley SD. Genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer. iScience 2023; 26:107569. [PMID: 37664588 PMCID: PMC10474475 DOI: 10.1016/j.isci.2023.107569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/24/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
Colorectal cancer (CRC) shows high incidence and mortality, partly due to the tumor microenvironment (TME), which is viewed as an active promoter of disease progression. Macrophages are among the most abundant cells in the TME. These immune cells are generally categorized as M1, with inflammatory and anti-cancer properties, or M2, which promote tumor proliferation and survival. Although the M1/M2 subclassification scheme is strongly influenced by metabolism, the metabolic divergence between the subtypes remains poorly understood. Therefore, we generated a suite of computational models that characterize the M1- and M2-specific metabolic states. Our models show key differences between the M1 and M2 metabolic networks and capabilities. We leverage the models to identify metabolic perturbations that cause the metabolic state of M2 macrophages to more closely resemble M1 cells. Overall, this work increases understanding of macrophage metabolism in CRC and elucidates strategies to promote the metabolic state of anti-tumor macrophages.
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Affiliation(s)
- Patrick E. Gelbach
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Stacey D. Finley
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA
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49
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Xiang L, Yang QL, Xie BT, Zeng HY, Ding LJ, Rao FQ, Yan T, Lu F, Chen Q, Huang XF. Dysregulated Arginine Metabolism Is Linked to Retinal Degeneration in Cep250 Knockout Mice. Invest Ophthalmol Vis Sci 2023; 64:2. [PMID: 37656476 PMCID: PMC10479211 DOI: 10.1167/iovs.64.12.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 08/04/2023] [Indexed: 09/02/2023] Open
Abstract
Purpose Degeneration of retinal photoreceptors is frequently observed in diverse ciliopathy disorders, and photoreceptor cilium gates the molecular trafficking between the inner and the outer segment (OS). This study aims to generate a homozygous global Cep250 knockout (KO) mouse and study the resulting phenotype. Methods We used Cep250 KO mice and untargeted metabolomics to uncover potential mechanisms underlying retinal degeneration. Long-term follow-up studies using optical coherence tomography (OCT) and electroretinography (ERG) were performed. Results OCT and ERG results demonstrated gradual thinning of the outer nuclear layer (ONL) and progressive attenuation of the scotopic ERG responses in Cep250-/- mice. More TUNEL signal was observed in the ONL of these mice. Immunostaining of selected OS proteins revealed mislocalization of these proteins in the ONL of Cep250-/- mice. Interestingly, untargeted metabolomics analysis revealed arginine-related metabolic pathways were altered and enriched in Cep250-/- mice. Mis-localization of a key protein in the arginine metabolism pathway, arginase 1 (ARG1), in the ONL of KO mice further supports this model. Moreover, adeno-associated virus (AAV)-based retinal knockdown of Arg1 led to similar architectural and functional alterations in wild-type retinas. Conclusions Altogether, these results suggest that dysregulated arginine metabolism contributes to retinal degeneration in Cep250-/- mice. Our findings provide novel insights that increase understanding of retinal degeneration in ciliopathy disorders.
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Affiliation(s)
- Lue Xiang
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qiao-Li Yang
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Bin-Tao Xie
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hui-Yi Zeng
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liu-Jun Ding
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Feng-Qin Rao
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- School of Pharmaceutical Sciences of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Tong Yan
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Fan Lu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qi Chen
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiu-Feng Huang
- Zhejiang Provincial Clinical Research Center for Pediatric Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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50
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Margolis EB, Maron G, Sun Y, Dallas RH, Allison KJ, Ferrolino J, Ross HS, Davis AE, Jia Q, Turner P, Mackay V, Morin CE, Triplett BM, Klein EJ, Englund JA, Tang L, Hayden RT. Microbiota Predict Infections and Acute Graft-Versus-Host Disease After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation. J Infect Dis 2023; 228:627-636. [PMID: 37249910 PMCID: PMC10469318 DOI: 10.1093/infdis/jiad190] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 04/19/2023] [Accepted: 05/27/2023] [Indexed: 05/31/2023] Open
Abstract
BACKGROUND Despite preventive measures, infections continue to pose significant risks to pediatric allogeneic hematopoietic cell transplantation (allo-HCT) recipients. The gut microbiota has been linked to clinical outcomes following adult allo-HCT. This study evaluated whether similar disruptions or differing microbiota patterns were associated with infection risk in pediatric allo-HCT. METHODS In a prospective observational study, fecal samples were obtained from 74 children before conditioning and upon neutrophil recovery. Microbiome signatures identified through sequencing were examined for their associations with infections or acute graft-versus-host disease (aGVHD) in the first-year post-HCT using Cox proportional hazards analysis. RESULTS Microbiome disruption in adults, did not predict infection risk in pediatric allo-HCT. Unique microbiota signatures were associated with different infections or aGVHD. A ratio of strict and facultative anaerobes (eg, Lachnoclostridium, Parabacteroides) prior to conditioning predicted bacteremia risk (Cox hazard ratio [HR], 3.89). A distinct ratio of oral (eg, Rothia, Veillonella) to intestinal anaerobes (eg, Anaerobutyricum, Romboutsia) at neutrophil recovery predicted likelihood of bacterial infections (Cox HR, 1.81) and viral enterocolitis (Cox HR, 1.96). CONCLUSIONS Interactions between medical interventions, pediatric hosts, and microbial communities contribute to microbiota signatures that predict infections. Further multicenter study is necessary to validate the generalizability of these ratios as biomarkers.
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Affiliation(s)
- Elisa B Margolis
- Department of Infectious Diseases, St Jude Children’s Research Hospital
- Department of Pediatrics, University of Tennessee Health Sciences Center
| | - Gabriela Maron
- Department of Infectious Diseases, St Jude Children’s Research Hospital
- Department of Pediatrics, University of Tennessee Health Sciences Center
| | - Yilun Sun
- Department of Biostatistics, St Jude Children’s Research Hospital
| | - Ronald H Dallas
- Department of Infectious Diseases, St Jude Children’s Research Hospital
| | - Kim J Allison
- Department of Infectious Diseases, St Jude Children’s Research Hospital
| | - Jose Ferrolino
- Department of Infectious Diseases, St Jude Children’s Research Hospital
| | - Hailey S Ross
- Department of Infectious Diseases, St Jude Children’s Research Hospital
| | - Amy E Davis
- Department of Infectious Diseases, St Jude Children’s Research Hospital
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, Memphis
| | - Qidong Jia
- Department of Infectious Diseases, St Jude Children’s Research Hospital
| | - Paige Turner
- Department of Infectious Diseases, St Jude Children’s Research Hospital
| | - Victoria Mackay
- Department of Infectious Diseases, St Jude Children’s Research Hospital
| | - Cara E Morin
- Division of Radiology and Medical Imaging, Cincinnati Children's Hospital, Ohio
| | - Brandon M Triplett
- Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children’s Research Hospital, Memphis, Tennessee
| | | | | | - Li Tang
- Department of Biostatistics, St Jude Children’s Research Hospital
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