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Yoshida S, Fujita Y, Koga T, Matsumoto H, Sumichika Y, Saito K, Sato S, Asano T, Kobayakawa M, Mizokami M, Sugiyama M, Migita K. Identification of novel cytokine to judge the diagnosis and clinical phenotype of adult-onset Still's disease. Immunol Med 2025; 48:58-69. [PMID: 39376199 DOI: 10.1080/25785826.2024.2411094] [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: 07/03/2024] [Accepted: 09/26/2024] [Indexed: 10/09/2024] Open
Abstract
This study aimed to identify biomarkers to distinguish adult-onset Still's disease (AOSD) and to predict disease phenotypes. In total, 49 patients diagnosed with AOSD and 200 patients with common diseases (controls) were included in the analysis. The levels of 69 cytokines were analyzed using a multi-suspension cytokine array. Cytokine cluster analysis was performed to identify specific molecular networks. Furthermore, random forest analysis and logistic regression analysis were used to rank cytokines based on their importance and to determine specific biomarkers for identification of AOSD patients and phenotypes. Patients with AOSD demonstrated significantly higher macrophage migration inhibitory factor (MIF) and interleukin (IL)-12(p40) serum levels than controls and patients with rheumatoid arthritis. Serum levels of chemokine (C-C motif) ligand (CCL) 8 and CCL22 were significantly lower in AOSD patients with a polycyclic systemic disease phenotype and could be differentiated with high accuracy from the other phenotypes (cutoff value for CCL8 = 122.7 pg/mL, CCL22 = 593.3 pg/mL, sensitivity 66.7%, specificity 87.1%, area under the curve 0.843). Combined MIF and IL-12(p40) levels may represent a biomarker for differentiating patients with AOSD from those with other diseases. The chemokine profiles of AOSD with a polycyclic systemic disease phenotype may differ from other phenotypes.
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Affiliation(s)
- Shuhei Yoshida
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yuya Fujita
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tomohiro Koga
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Haruki Matsumoto
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yuya Sumichika
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kenji Saito
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shuzo Sato
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tomoyuki Asano
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Masao Kobayakawa
- Department of Endoscopy, Fukushima Medical University Hospital, Fukushima, Japan
- Medical Research Center, Fukushima Medical University, Fukushima, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masaya Sugiyama
- Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Kiyoshi Migita
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
- Department of Rheumatology, St. Francis Hospital, Nagasaki, Japan
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Pressley KR, Naseem Y, Nalawade S, Forsthuber TG. The distinct functions of MIF in inflammatory cardiomyopathy. Front Immunol 2025; 16:1544484. [PMID: 40092999 PMCID: PMC11906721 DOI: 10.3389/fimmu.2025.1544484] [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: 12/12/2024] [Accepted: 02/10/2025] [Indexed: 03/19/2025] Open
Abstract
The immune system plays a crucial role in cardiac homeostasis and disease, and the innate and adaptive immune systems can be beneficial or detrimental in cardiac injury. The pleiotropic proinflammatory cytokine macrophage migration inhibitory factor (MIF) is involved in the pathogenesis of many human disease conditions, including heart diseases and inflammatory cardiomyopathies. Inflammatory cardiomyopathies are frequently observed after microbial infection but can also be caused by systemic immune-mediated diseases, drugs, and toxic substances. Immune cells and MIF are implicated in many of these conditions and may affect progression of inflammatory cardiomyopathy (ICM) to myocardial remodeling and dilated cardiomyopathy (DCM). The potential for targeting MIF therapeutically in patients with inflammatory diseases is an active area of investigation. Here we review the current literature supporting the role(s) of MIF in ICM and cardiac dysfunction. We posit that future research to further elucidate the underlying functions of MIF in cardiac pathologies is warranted.
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Affiliation(s)
- Kyle R. Pressley
- Department of Molecular Microbiology and Immunology, University of Texas at San Antonio, San Antonio, TX, United States
- Department of Neuroscience, Developmental and Regenerative Biology, University of Texas at San Antonio, San Antonio, TX, United States
| | - Yashfa Naseem
- Department of Molecular Microbiology and Immunology, University of Texas at San Antonio, San Antonio, TX, United States
| | - Saisha Nalawade
- Department of Pre-clinical Immunology, Corner Therapeutics, Watertown, MA, United States
| | - Thomas G. Forsthuber
- Department of Molecular Microbiology and Immunology, University of Texas at San Antonio, San Antonio, TX, United States
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Wu H, Yin F, Wang Y, Tang Z, Hong H, Jiang T, Guo J, Ma X, Yao G, Zhang H. Increased macrophage migration inhibitory factor is associated with inflammation in patients with rheumatoid arthritis. Clin Rheumatol 2025:10.1007/s10067-025-07361-8. [PMID: 39953337 DOI: 10.1007/s10067-025-07361-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 01/21/2025] [Accepted: 01/26/2025] [Indexed: 02/17/2025]
Abstract
OBJECTIVE The macrophage migration inhibitory factor (MIF) in the plasma, hydrops articuli, and synovium, and its relationship with laboratory indexes in patients with rheumatoid arthritis (RA) were determined, for the purpose to reveal the role of MIF on the pathogenesis of RA. METHODS MIF mRNA expression in PBMCs was detected by qPCR. Plasma MIF was measured by enzyme linked immunosorbent assay (ELISA). MIF in hydrops articuli and synovium from RA patients and OA patients was evaluated by immunofluorescence (IF) and immunohistochemistry (IHC). The relationship between MIF and laboratory indexes of RA patients was analyzed. Human fibroblast-like synoviocytes (FLS) were treated with recombinant human MIF, and expression of inflammatory factors was determined by qPCR. The matrix metalloproteinase (MMP) 9 and extracellular regulated protein kinases (ERK)1/2 in FLS with MIF treatment were detected. RESULTS MIF is significantly increased in plasma and hydrops articuli in RA patients. The expression of multiple inflammatory factors and MMPs was increased in RA patients and in FLS with rhMIF treatment. MIF was correlated with laboratory indexes in RA patients. Mechanistically, MIF promoted production of MMP9 by FLS through the ERK1/2 pathway. CONCLUSION Our results indicated that increased MIF was correlated with disease activity of RA patients. These findings also suggested that MIF induced multiple inflammatory factors and MMP 9 in FLS via ERK 1/2 pathway. Key Points • MIF plays a key role in the initiation of RA by promoting the expression of various inflammatory factors in FLS and MMPs. • This study provides a basis for MIF-targeted RA clinical therapy and for exploring the feasibility of MIF as a therapeutic target for RA. • Increased MIF correlates with disease activity in RA patients.
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Affiliation(s)
- Haolin Wu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Fanzhang Yin
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Yue Wang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Zhicheng Tang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Huiming Hong
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Tingting Jiang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Junqiao Guo
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Xiaolei Ma
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Genhong Yao
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
| | - Huayong Zhang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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Uhm C, Gu J, Ju W, Pizzella S, Oktay H, Peng JYC, Guariglia S, Liu Y, Zhao H, Wang Y, Menon R, Zhong N. Single-nucleus RNA sequencing reveals distinct pathophysiological trophoblast signatures in spontaneous preterm birth subtypes. Cell Biosci 2025; 15:1. [PMID: 39773245 PMCID: PMC11705668 DOI: 10.1186/s13578-024-01343-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Spontaneous preterm birth (sPTB) poses significant challenges, affecting neonatal health and neurodevelopmental outcomes worldwide. The specific effects of placental trophoblasts on the pathological development of sPTB subtypes-preterm premature rupture of fetal membranes (pPROM) and spontaneous preterm labor (sPTL)-are not fully understood, making it crucial to uncover these impacts for the development of effective therapeutic strategies. Using single-nucleus RNA sequencing, we investigated transcriptomic and cellular differences at the maternal-fetal interface in pPROM and sPTL placentas. Our findings revealed distinct trophoblast compositions with pPROM characterized predominantly by extravillous trophoblasts (EVTs), while sPTL showed an abundance of syncytiotrophoblasts (STBs). Through cell differentiation and cell-to-cell communication analyses, other distinguishing factors were also found. In pPROM, heightened inflammation, oxidative stress, and vascular dysregulation with key pathways including tumor necrosis factor signaling, matrix metalloproteinase activation, and integrin-mediated cell adhesion, highlighted an invasive EVT profile potentially driven by hypoxic conditions and immune cell recruitment. In contrast, sPTL was marked by increased smooth muscle contraction, vascular remodeling, and altered signaling dynamics involving fibroblasts, including TGF-β and WNT pathways. Our study highlights the critical need to distinguish sPTB subtypes to improve diagnostic precision and therapeutic targeting. The molecular insights gained provide a foundation for future investigations aimed at functional validation of key pathways and exploration of trophoblasts on the development of sPTB. Ultimately, these findings pave the way for more personalized and effective interventions to mitigate adverse outcomes associated with preterm birth.
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Affiliation(s)
- Cherilyn Uhm
- New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA
| | - Jianlei Gu
- School of Public Health, Yale University, New Haven, CT, 06520-0834, USA
| | - Weina Ju
- New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA
| | - Stephanie Pizzella
- Department of Obstetrics and Gynecology, School of Medicine, Washington University, St. Louis, MO, 63110-1010, USA
| | - Hande Oktay
- New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA
| | | | - Sararose Guariglia
- New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA
| | - Yong Liu
- New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA
| | - Hongyu Zhao
- School of Public Health, Yale University, New Haven, CT, 06520-0834, USA
| | - Yong Wang
- Department of Obstetrics and Gynecology, School of Medicine, Washington University, St. Louis, MO, 63110-1010, USA
| | - Ramkumar Menon
- The University of Texas Medical Branch at Galveston, Galveston, TX, 77555-0144, USA
| | - Nanbert Zhong
- New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA.
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Zhao L, Zhao BH, Ruze A, Li QL, Deng AX, Gao XM. Distinct roles of MIF in the pathogenesis of ischemic heart disease. Cytokine Growth Factor Rev 2024; 80:121-137. [PMID: 39438226 DOI: 10.1016/j.cytogfr.2024.10.005] [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: 08/28/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/25/2024]
Abstract
The role of macrophage migration inhibitory factor (MIF) as a multifunctional cytokine in immunomodulation and inflammatory response is increasingly appreciated. Ischemic heart disease (IHD), the leading cause of global mortality, remains a focal point of research owing to its intricate pathophysiology. MIF has been identified as a critical player in IHD, where it exerts distinct roles. On one hand, MIF plays a protective role by enhancing energy metabolism through activation of AMPK, resisting oxidative stress, inhibiting activation of the JNK pathway, and maintaining intracellular calcium ion homeostasis. Additionally, MIF exerts protective effects through mesenchymal stem cells and exosomes. On the other hand, MIF can assume a pro-inflammatory role, which contributes to the exacerbation of IHD's development and progression. Furthermore, MIF levels significantly increase in IHD patients, and its genetic polymorphisms are positively correlated with prevalence and severity. These findings position MIF as a potential biomarker and therapeutic target in the management of IHD. This review summarizes the structure, source, signaling pathways and biological functions of MIF and focuses on its roles and clinical characteristics in IHD. The genetic variants of MIF associated with IHD is also discussed, providing more understandings of its complex interplay in the disease's pathology.
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Affiliation(s)
- Ling Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Bang-Hao Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Amanguli Ruze
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Qiu-Lin Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - An-Xia Deng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Xiao-Ming Gao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China; Xinjiang Key Laboratory of Cardiovascular Disease, Urumqi, China.
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Zhang F, Meng T, Feng R, Jin C, Zhang S, Meng J, Zhang M, Liang C. MIF aggravates experimental autoimmune prostatitis through activation of the NLRP3 inflammasome via the PI3K/AKT pathway. Int Immunopharmacol 2024; 141:112891. [PMID: 39153310 DOI: 10.1016/j.intimp.2024.112891] [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] [Revised: 07/17/2024] [Accepted: 08/05/2024] [Indexed: 08/19/2024]
Abstract
In our investigation, we investigated the role of macrophage migration inhibitory factor (MIF), a key cytokine, in chronic nonbacterial prostatitis (CNP), an underexplored pathology. Elevated MIF expression was observed in the serum of individuals with chronic prostatitis-like symptoms (CP-LS) as well as in serum and tissue samples from experimental autoimmune prostatitis (EAP) mouse model. Treatment with ISO-1, a specific MIF antagonist, effectively mitigated prostatic inflammation and macrophage infiltration, thereby emphasizing the critical role of MIF in orchestrating immune responses within the prostate microenvironment. Further analyses revealed that MIF stimulates the PI3K/AKT and NLRP3 inflammasome pathways, which are integral to inflammation and cellular immunity. Pharmacological inhibition of the PI3K/AKT pathway by LY294002 substantially reduced prostatic inflammation and macrophage infiltration, potentially by inhibiting NLRP3 inflammasome activation. These findings collectively suggest that MIF is a potential diagnostic marker for CNP and suggest that targeting MIF or its downstream signalling pathways, PI3K/AKT and NLRP3, might represent a novel therapeutic strategy for this condition.
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Affiliation(s)
- Fei Zhang
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China
| | - Tong Meng
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China
| | - Rui Feng
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China; Department of Urology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Chen Jin
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China
| | - Song Zhang
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China
| | - Jialin Meng
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China
| | - Meng Zhang
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China.
| | - Chaozhao Liang
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China.
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Li J, Zhu X, Zhu W, Li L, Wei H, Zhang S. Research Progress on the Impact of Human Chorionic Gonadotropin on Reproductive Performance in Sows. Animals (Basel) 2024; 14:3266. [PMID: 39595318 PMCID: PMC11591456 DOI: 10.3390/ani14223266] [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: 09/27/2024] [Revised: 11/01/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Human chorionic gonadotropin is a glycoprotein hormone produced by human or humanoid syncytiotrophoblasts that differentiate during pregnancy. Due to its superior stability and long-lasting effects compared to luteinizing hormone, it is often used to replace luteinizing hormone to regulate reproductive performance in sows. Human chorionic gonadotropin promotes oocyte maturation, follicle development, and luteinization, thereby increasing conception rates and supporting early embryonic development. In sow reproductive management, the application of human chorionic gonadotropin not only enhances ovulation synchrony but also improves the success rate of embryo implantation by regulating endometrial receptivity and immune mechanisms, significantly enhancing overall reproductive performance. This article primarily reviews the application of human chorionic gonadotropin in sow follicle development, luteal maintenance, and embryo implantation, providing theoretical support for its use in improving reproductive performance in sows.
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Affiliation(s)
| | | | | | | | | | - Shouquan Zhang
- State Key Laboratory of Swine and Poultry Breeding Industry, National Engineering Research Center for Breeding Swine Industry, Guangdong Provincial Key Lab of Agroanimal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510640, China; (J.L.); (X.Z.); (W.Z.); (L.L.); (H.W.)
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Wang L, Nakamura A. Macrophage migration inhibitory factor as a potential 'missing important factor' driving inflammatory arthritis in adrenocorticotropic hormone deficiency. Mod Rheumatol Case Rep 2024:rxae070. [PMID: 39656882 DOI: 10.1093/mrcr/rxae070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 11/10/2024] [Indexed: 12/17/2024]
Affiliation(s)
- Lisa Wang
- Division of Rheumatology, Department of Medicine, Queen's University, Kingston, ON, Canada
- Faculty of Health Sciences, School of Medicine, Queen's University, Kingston, ON, Canada
| | - Akihiro Nakamura
- Division of Rheumatology, Department of Medicine, Queen's University, Kingston, ON, Canada
- Faculty of Health Sciences, School of Medicine, Queen's University, Kingston, ON, Canada
- Department of Medicine, Translational Institute of Medicine, Queen's University, Kingston, ON, Canada
- Rheumatology Clinic, Kingston Health Science Centre, Kingston, ON, Canada
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Rivera LA, Hernández PE, Vannan DT, Reyes JL, Rodríguez T, Sánchez-Barrera Á, González MI, Bustos J, Ramos OA, Juárez I, Rodriguez-Sosa M, Vázquez A. Macrophage Migration Inhibitory Factor (MIF) is a Key Player in Dry Eye Disease. Ocul Immunol Inflamm 2024; 32:1707-1721. [PMID: 38127798 DOI: 10.1080/09273948.2023.2290624] [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: 08/03/2023] [Revised: 11/09/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023]
Abstract
PURPOSE To explore the role of the proinflammatory cytokine, macrophage migration inhibitory factor (MIF), in a murine model of dry eye disease (DED). METHODS The role of MIF on DED was determined using genetically MIF deficient mice and pharmacological inhibition of MIF. DED was induced with 0.5 mg of scopolamine via subcutaneous injection in wild type (WT) and mice lacking MIF (Mif-/-), three times a day for 21 days. DED signs, tear volume, ferning pattern and cytology impression were evaluated. Also, eye tissues were collected to determine transcripts of key inflammatory mediators and histopathological damage. In a second set of experiments, we neutralized MIF with ISO-1, an isozaxiline-derivative MIF tautomerase activity-inhibiting small molecule in WT mice, following an acute DED model for 10 days. ISO-1 was given starting on day 3 after DED induction and signs were evaluated, including a recovery phase in both experimental approaches. RESULTS When compared to WT, Mif-/- mice showed attenuated signs of DED like preserved mucin pattern and increased tear volume. Also, Mif-/- mice maintained conjunctival epithelial cells and less corneal damage, associated with lower levels of TNFα and IL-1β. At recovery phase, Mif-/- mice presented improved signs. Interestingly, in cornea and conjunctiva the absence of MIF selectively downregulated the transcription of inflammatory enzymes like inos and nox4 whereas displayed enhanced transcripts of il-4, il-13, tgfβ and cox2. Finally, pharmacological inhibition of MIF using ISO-1, replicated the above findings in the mouse model. CONCLUSION MIF is a central positive mediator of the inflammatory process in experimental DED, thus, targeting MIF could be used as a novel therapy in ocular surface inflammatory pathologies.
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Affiliation(s)
- Luis A Rivera
- Laboratorio de Enfermedades Inflamatorias Oculares, Carrera de Optometría, FES Iztacala, UNAM, Tlalnepantla de Baz, México
| | - Pablo E Hernández
- Laboratorio de Enfermedades Inflamatorias Oculares, Carrera de Optometría, FES Iztacala, UNAM, Tlalnepantla de Baz, México
| | - Danielle T Vannan
- Boston Scientific, 300 Boston Scientific Way, Marlborough, Massachusetts, USA
| | - José L Reyes
- Laboratorio de Inmunología Experimental y Regulación de la Inflamación Hepato-Intestinal, UBIMED, FES Iztacala, UNAM, Tlalnepantla de Baz, México
| | - Tonathiu Rodríguez
- Laboratorio de Enfermedades Inflamatorias Oculares, Carrera de Optometría, FES Iztacala, UNAM, Tlalnepantla de Baz, México
| | - Ángel Sánchez-Barrera
- Laboratorio de Inmunoparasitología, UBIMED, FES Iztacala, UNAM, Tlalnepantla de Baz, México
| | - Marisol I González
- Laboratorio de Inmunología Experimental y Regulación de la Inflamación Hepato-Intestinal, UBIMED, FES Iztacala, UNAM, Tlalnepantla de Baz, México
| | - José Bustos
- Laboratorio de Biología Molecular e Inmunología de Arbovirus, UBIMED, FES Iztacala, UNAM, Tlalnepantla de Baz, Estado de México
| | - Oscar A Ramos
- Laboratorio de Enfermedades Inflamatorias Oculares, Carrera de Optometría, FES Iztacala, UNAM, Tlalnepantla de Baz, México
| | - Imelda Juárez
- Laboratorio de Inmunidad Innata, UBIMED, FES Iztacala, UNAM, Tlalnepantla de Baz, México
| | - Miriam Rodriguez-Sosa
- Laboratorio de Inmunidad Innata, UBIMED, FES Iztacala, UNAM, Tlalnepantla de Baz, México
| | - Alicia Vázquez
- Laboratorio de Enfermedades Inflamatorias Oculares, Carrera de Optometría, FES Iztacala, UNAM, Tlalnepantla de Baz, México
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Fang T, Liu L, Song D, Huang D. The role of MIF in periodontitis: A potential pathogenic driver, biomarker, and therapeutic target. Oral Dis 2024; 30:921-937. [PMID: 36883414 DOI: 10.1111/odi.14558] [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: 01/03/2023] [Revised: 02/08/2023] [Accepted: 03/01/2023] [Indexed: 03/09/2023]
Abstract
OBJECTIVE Periodontitis is an inflammatory disease that involves an imbalance in the oral microbiota, activation of inflammatory and immune responses, and alveolar bone destruction. Macrophage migration inhibitory factor (MIF) is a versatile cytokine involved in several pathological reactions, including inflammatory processes and bone destruction, both of which are characteristics of periodontitis. While the roles of MIF in cancer and other immune diseases have been extensively characterized, its role in periodontitis remains inconclusive. RESULTS In this review, we describe a comprehensive analysis of the potential roles of MIF in periodontitis from the perspective of immune response and bone regulation at the cellular and molecular levels. Moreover, we discuss its potential reliability as a novel diagnostic and therapeutic target for periodontitis. CONCLUSION This review can aid dental researchers and clinicians in understanding the current state of MIF-related pathogenesis, diagnosis, and treatment of periodontitis.
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Affiliation(s)
- Tongfeng Fang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Liu Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Conservative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Dongzhe Song
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Conservative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Dingming Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Conservative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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11
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Patel J, Dawson VL, Dawson TM. Blocking the Self-Destruct Program of Dopamine Neurons through Macrophage Migration Inhibitory Factor Nuclease Inhibition. Mov Disord 2024; 39:644-650. [PMID: 38396375 PMCID: PMC11160583 DOI: 10.1002/mds.29748] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/10/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and non-motor symptoms. Given the insurmountable burden of this disease on the population and healthcare system, significant efforts have been put forth toward generating disease modifying therapies. This class of treatments characteristically alters disease course, as opposed to current strategies that focus on managing symptoms. Previous literature has implicated the cell death pathway known as parthanatos in PD progression. Inhibition of this pathway by targeting poly (ADP)-ribose polymerase 1 (PARP1) prevents neurodegeneration in a model of idiopathic PD. However, PARP1 has a vast repertoire of functions within the body, increasing the probability of side effects with the long-term treatment likely necessary for clinically significant neuroprotection. Recent work culminated in the development of a novel agent targeting the macrophage migration inhibitory factor (MIF) nuclease domain, also named parthanatos-associated apoptosis-inducing factor nuclease (PAAN). This nuclease activity specifically executes the terminal step in parthanatos. Parthanatos-associated apoptosis-inducing factor nuclease inhibitor-1 was neuroprotective in multiple preclinical mouse models of PD. This piece will focus on contextualizing this discovery, emphasizing its significance, and discussing its potential implications for parthanatos-directed treatment. © 2024 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Jaimin Patel
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Valina L. Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ted M. Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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12
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Singh I, Hoti SL, Chauhan N, Joshi RK, Prasad TSK, Sarikhani M, Kaushik M, Unger BS, Jadhav P, Modi PK. Immunomodulation of streptozotocin induced Type 1 diabetes mellitus in mouse model by Macrophage migration inhibitory factor-2 (MIF-2) homologue of human lymphatic filarial parasite, Wuchereria bancrofti. Acta Trop 2024; 252:107142. [PMID: 38331083 DOI: 10.1016/j.actatropica.2024.107142] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 02/05/2024] [Accepted: 02/05/2024] [Indexed: 02/10/2024]
Abstract
Helminth parasites modulate the host immune system to ensure a long-lasting asymptomatic form of infection generally, mediated by the secretion of immunomodulatory molecules and one such molecule is a homologue of human host cytokine, Macrophage migratory Inhibitory Factor (hMIF). In this study, we sought to understand the role of homologue of hMIF from the lymphatic filarial parasite, Wuchereria bancrofti (Wba-MIF2), in the immunomodulation of the Streptozotocin (STZ)-induced Type1 Diabetes Mellitus (T1DM) animal model. Full-length recombinant Wba-MIF2 was expressed and found to have both oxidoreductase and tautomerase activities. Wba-MIF2 recombinant protein was treated to STZ induced T1DM animals, and after 5 weeks pro-inflammatory (IL-1, IL-2, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4, IL-10) cytokines and gene expressions were determined in sera samples and spleen respectively. Pro-inflammatory and anti-inflammatory cytokine levels were significantly (p<0.05) up-regulated and down-regulated respectively, in the STZ-T1DM animals, as compared to treated groups. Histopathology showed macrophage infiltration and greater damage of islets of beta cells in the pancreatic tissue of STZ-T1DM animals, than Wba-MIF2 treated STZ-T1DM animals. The present study clearly showed the potential of Wba-MIF2 as an immunomodulatory molecule, which could modulate the host immune system in the STZ-T1DM mice model from a pro-inflammatory to anti-inflammatory milieu.
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Affiliation(s)
- Ishwar Singh
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India; KLE Academy of Higher Education and Research, Belagavi 590010, India Karnataka, India
| | - S L Hoti
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India.
| | - Nikhil Chauhan
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India
| | - R K Joshi
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India
| | - T S Keshava Prasad
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575007, Karnataka, India
| | | | - Meenakshi Kaushik
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India
| | - Banappa S Unger
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India
| | - Pankaj Jadhav
- Indian Institute of Science, Bangalore 560012, Karnataka, India
| | - Prashant Kumar Modi
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575007, Karnataka, India
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13
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Chua C, Mahamed D, Nkongolo S, Sanchez Vasquez JD, Mehrotra A, Wong DKH, Chung RT, Feld JJ, Janssen HLA, Gehring AJ. Liver-restricted Type I IFN Signature Precedes Liver Damage in Chronic Hepatitis B Patients Stopping Antiviral Therapy. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1002-1011. [PMID: 38294274 DOI: 10.4049/jimmunol.2300569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 01/01/2024] [Indexed: 02/01/2024]
Abstract
Immune-mediated liver damage is the driver of disease progression in patients with chronic hepatitis B virus (HBV) infection. Liver damage is an Ag-independent process caused by bystander activation of CD8 T cells and NK cells. How bystander lymphocyte activation is initiated in chronic hepatitis B patients remains unclear. Periods of liver damage, called hepatic flares, occur unpredictably, making early events difficult to capture. To address this obstacle, we longitudinally sampled the liver of chronic hepatitis B patients stopping antiviral therapy and analyzed immune composition and activation using flow cytometry and single-cell RNA sequencing. At 4 wk after stopping therapy, HBV replication rebounded but no liver damage was detectable. There were no changes in cell frequencies at viral rebound. Single-cell RNA sequencing revealed upregulation of IFN-stimulated genes (ISGs) and proinflammatory cytokine migration inhibitory factor (MIF) at viral rebound in patients that go on to develop hepatic flares 6-18 wk after stopping therapy. The type I IFN signature was only detectable within the liver, and neither IFN-α/β or ISG induction could be detected in the peripheral blood. In vitro experiments confirmed the type I IFN-dependent ISG profile whereas MIF was induced primarily by IL-12. MIF exposure further amplified inflammatory cytokine production by myeloid cells. Our data show that innate immune activation is detectable in the liver before clinically significant liver damage is evident. The combination of type I IFN and enhanced cytokine production upon MIF exposure represent the earliest immunological triggers of lymphocyte bystander activation observed in hepatic flares associated with chronic HBV infection.
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Affiliation(s)
- Conan Chua
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Deeqa Mahamed
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Shirin Nkongolo
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Internal Medicine IV (Gastroenterology, Hepatology, Infectious Diseases), University Hospital Heidelberg, Heidelberg, Germany
| | - Juan Diego Sanchez Vasquez
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Aman Mehrotra
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - David K H Wong
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | | | - Jordan J Feld
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Adam J Gehring
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
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14
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Murata R, Watanabe H, Iwakiri R, Chikamatsu M, Satoh T, Noguchi I, Yasuda K, Nishinoiri A, Yoshitake T, Nosaki H, Maeda H, Maruyama T. Albumin-fused thioredoxin ameliorates high-fat diet-induced non-alcoholic steatohepatitis. Heliyon 2024; 10:e25485. [PMID: 38352801 PMCID: PMC10861950 DOI: 10.1016/j.heliyon.2024.e25485] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/04/2024] [Accepted: 01/29/2024] [Indexed: 02/16/2024] Open
Abstract
The pathogenesis of non-alcoholic steatohepatitis (NASH) involves the simultaneous interaction of multiple factors such as lipid accumulation, oxidative stress, and inflammatory response. Here, the effect of human serum albumin (HSA) fused to thioredoxin (Trx) on NASH was investigated. Trx is known to have anti-oxidative, anti-inflammatory, and anti-apoptotic effects. However, Trx is a low molecular weight protein and is rapidly eliminated from the blood. To overcome the low availability of Trx, HSA-Trx fusion protein was produced and evaluated the therapeutic effect on high-fat diet (HFD)-induced NASH model mice. HSA-Trx administered before the formation of NASH pathology showed it to have a preventive effect. Specifically, HSA-Trx was found to prevent the pathological progression to NASH by suppressing lipid accumulation, liver injury markers, and liver fibrosis. When HSA-Trx was administered during the early stage of NASH there was a marked reduction in lipid accumulation, inflammation, and fibrosis in the liver, indicating that HSA-Trx ameliorates NASH pathology. The findings indicate that HSA-Trx influences multiple pathological factors, such as oxidative stress, inflammation, and apoptosis, to elicit a therapeutic benefit. HSA-Trx also inhibited palmitic acid-induced lipotoxicity in HepG2 cells. Taken together, these results indicate that HSA-Trx has potential as a therapeutic agent for NASH pathology.
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Affiliation(s)
- Ryota Murata
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Hiroshi Watanabe
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Ryotaro Iwakiri
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Mayuko Chikamatsu
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Takao Satoh
- Kumamoto Industrial Research Institute, Kumamoto, Japan
| | - Isamu Noguchi
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Kengo Yasuda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Ayano Nishinoiri
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Takuma Yoshitake
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Hiroto Nosaki
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Hitoshi Maeda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan
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15
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Zhang H, Zhang X, Li H, Wang B, Chen P, Meng J. The roles of macrophage migration inhibitory factor in retinal diseases. Neural Regen Res 2024; 19:309-315. [PMID: 37488883 PMCID: PMC10503606 DOI: 10.4103/1673-5374.379020] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/07/2023] [Accepted: 04/28/2023] [Indexed: 07/26/2023] Open
Abstract
Macrophage migration inhibitory factor (MIF), a multifunctional cytokine, is secreted by various cells and participates in inflammatory reactions, including innate and adaptive immunity. There are some evidences that MIF is involved in many vitreoretinal diseases. For example, MIF can exacerbate many types of uveitis; measurements of MIF levels can be used to monitor the effectiveness of uveitis treatment. MIF also alleviates trauma-induced and glaucoma-induced optic nerve damage. Furthermore, MIF is critical for retinal/choroidal neovascularization, especially complex neovascularization. MIF exacerbates retinal degeneration; thus, anti-MIF therapy may help to mitigate retinal degeneration. MIF protects uveal melanoma from attacks by natural killer cells. The mechanism underlying the effects of MIF in these diseases has been demonstrated: it binds to cluster of differentiation 74, inhibits the c-Jun N-terminal kinase pathway, and triggers mitogen-activated protein kinases, extracellular signal-regulated kinase-1/2, and the phosphoinositide-3-kinase/Akt pathway. MIF also upregulates Toll-like receptor 4 and activates the nuclear factor kappa-B signaling pathway. This review focuses on the structure and function of MIF and its receptors, including the effects of MIF on uveal inflammation, retinal degeneration, optic neuropathy, retinal/choroidal neovascularization, and uveal melanoma.
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Affiliation(s)
- Hongbing Zhang
- Shaanxi Institute of Ophthalmology, Xi’an, Shaanxi Province, China
- Department of Ophthalmology, First Affiliated Hospital of Northwest University, Xi’an, Shaanxi Province, China
| | - Xianjiao Zhang
- Department of Pathology, First Affiliated Hospital of Northwest University, Xi’an, Shaanxi Province, China
| | - Hongsong Li
- Department of Ophthalmology, First Affiliated Hospital of Northwest University, Xi’an, Shaanxi Province, China
| | - Bing Wang
- Department of Ophthalmology, First Affiliated Hospital of Northwest University, Xi’an, Shaanxi Province, China
| | - Pei Chen
- Department of Ophthalmology, First Affiliated Hospital of Northwest University, Xi’an, Shaanxi Province, China
| | - Jiamin Meng
- Department of Ophthalmology, First Affiliated Hospital of Northwest University, Xi’an, Shaanxi Province, China
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16
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Wright MA, Giurgescu C, Misra DP, Slaughter-Acey JC, Engeland CG. Neighborhood racial composition and experiences of racial discrimination: Associations with cytokines during pregnancy among African American women. Brain Behav Immun Health 2024; 35:100715. [PMID: 38193096 PMCID: PMC10771980 DOI: 10.1016/j.bbih.2023.100715] [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: 07/19/2023] [Revised: 12/08/2023] [Accepted: 12/08/2023] [Indexed: 01/10/2024] Open
Abstract
Background Preterm birth rates are consistently higher in African American (AA) pregnancies compared to White pregnancies in the United States. Neighborhood racial composition, experiences of racial discrimination, and systemic inflammation are factors that have been associated with preterm birth and other adverse pregnancy outcomes that may account for these disparities. Here, we investigated whether perceived neighborhood racial composition and experiences of discrimination were predictive of cytokine levels during pregnancy among AA individuals. Methods 545 AA individuals completed surveys and had blood samples collected at prenatal clinics in the Midwest at three timepoints (8-18,19-29, and 30-36 weeks gestation) throughout pregnancy. Pro-inflammatory [interferon (IFN)-γ, interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, macrophage migration inhibitory factor (MIF)] and anti-inflammatory cytokines (IL-10) were quantified. Multivariate and multilevel models were used to examine associations of perceived neighborhood racial composition and experiences of racial discrimination with cytokine levels, controlling for relevant covariates. Results Perceived neighborhood racial composition was significantly associated with MIF at 30-36 weeks gestation in multivariate regression (p < 0.001). Living in neighborhoods with more compared to fewer White people was predictive of higher levels of MIF (b = 0.599, SE = 0.12, p < 0.001). Experiences of discrimination were also associated with higher levels of MIF (β = 0.141, SE = 0.07, p = 0.036). Neither predictor was associated with other cytokines. Follow-up analyses revealed that neighborhood racial composition was also predictive of higher MIF levels at 8-18 weeks gestation (p = 0.02) and at 19-29 weeks gestation (p = 0.04). Conclusions Living in neighborhoods with more White individuals and having more lifetime experiences of racial discrimination were positively related to levels of the pro-inflammatory cytokine, MIF, among pregnant AA individuals. MIF's known positive relationships with chronic stress and preterm birth suggest that these elevations in MIF may have negative health consequences. Future studies should explore whether MIF serves as a pathway between neighborhood racial composition or experiences of racial discrimination and preterm birth risk among AA individuals.
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Affiliation(s)
- Molly A. Wright
- Department of Biobehavioral Health, College of Health and Human Development, The Pennsylvania State University, University Park, PA, USA
| | - Carmen Giurgescu
- College of Nursing, University of Central Florida, Orlando, FL, USA
| | - Dawn P. Misra
- Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Jaime C. Slaughter-Acey
- Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA
| | - Christopher G. Engeland
- Department of Biobehavioral Health, College of Health and Human Development, The Pennsylvania State University, University Park, PA, USA
- Ross and Carol Nese College of Nursing, The Pennsylvania State University, University Park, PA, USA
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Talreja J, Peng C, Samavati L. MIF modulates p38/ERK phosphorylation via MKP-1 induction in sarcoidosis. iScience 2024; 27:108746. [PMID: 38299032 PMCID: PMC10829885 DOI: 10.1016/j.isci.2023.108746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 09/21/2023] [Accepted: 12/12/2023] [Indexed: 02/02/2024] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a versatile cytokine that influences a variety of cellular processes important for immune regulation and tissue homeostasis. Sarcoidosis is a granulomatous disease characterized by extensive local inflammation and increased T helper cell mediated cytokines. We have shown that MIF has a modulatory role in cytokine networks in sarcoidosis. We investigated the effect of exogenous MIF on sarcoidosis alveolar macrophages (AMs), CD14+ monocytes and peripheral blood mononuclear cells (PBMCs). Our results showed that MIF negatively regulates the increased MAPKs (pp38 and pERK1/2) activation by inducing Mitogen-activated protein kinase phosphatase (MKP)-1. We found that MIF decreased IL-6 and IL-1β production, increased the percentage of regulatory T-cells (Tregs), and induced IL-1R antagonist (IL-1RA) and IL-10 production. Thus, the results of our study suggest that exogenous MIF modulates MAPK activation by inducing MKP-1and Tregs as well as IL-10 and IL-1RA, and hence plays a modulatory role in immune activation in sarcoidosis.
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Affiliation(s)
- Jaya Talreja
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University, School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA
| | - Changya Peng
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University, School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA
| | - Lobelia Samavati
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University, School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA
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18
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Matejuk A, Benedek G, Bucala R, Matejuk S, Offner H, Vandenbark AA. MIF contribution to progressive brain diseases. J Neuroinflammation 2024; 21:8. [PMID: 38178143 PMCID: PMC10765708 DOI: 10.1186/s12974-023-02993-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 12/12/2023] [Indexed: 01/06/2024] Open
Abstract
Progressive brain diseases create a huge social and economic burden on modern societies as a major cause of disability and death. Incidence of brain diseases has a significantly increasing trend and merits new therapeutic strategies. At the base of many progressive brain malfunctions is a process of unresolved, chronic inflammation. Macrophage migration inhibitory factor, MIF, is an inflammatory mediator that recently gained interest of neuro-researchers due to its varied effects on the CNS such as participation of nervous system development, neuroendocrine functions, and modulation of neuroinflammation. MIF appears to be a candidate as a new biomarker and target of novel therapeutics against numerous neurologic diseases ranging from cancer, autoimmune diseases, vascular diseases, neurodegenerative pathology to psychiatric disorders. In this review, we will focus on MIF's crucial role in neurological diseases such as multiple sclerosis (MS), Alzheimer's disease (AD) and glioblastoma (GBM).
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Affiliation(s)
- Agata Matejuk
- Department of Immunology, Collegium Medicum, University of Zielona Góra, Zielona Góra, Poland.
| | - Gil Benedek
- Tissue Typing and Immunogenetics Unit, Department of Genetics, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Richard Bucala
- Department of Internal Medicine, Section of Rheumatology, Allergy and Immunology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | | | - Halina Offner
- Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW U.S. Veterans Hospital Rd., Portland, OR, 97239, USA
- Department of Neurology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA
- Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA
| | - Arthur A Vandenbark
- Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW U.S. Veterans Hospital Rd., Portland, OR, 97239, USA.
- Department of Neurology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA.
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA.
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19
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Rupp A, Bahlmann S, Trimpop N, von Pawel J, Holdenrieder S. Lack of clinical utility of serum macrophage migration inhibitory factor (MIF) for monitoring therapy response and estimating prognosis in advanced lung cancer. Tumour Biol 2024; 46:S341-S353. [PMID: 37545291 DOI: 10.3233/tub-230006] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND Lung cancer is a major burden to global health and is still among the most frequent and most lethal malignant diseases. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in a variety of processes including tumorigenesis, formation of a tumor microenvironment and metastasis. It is therefore a potential prognostic biomarker in malignant diseases. OBJECTIVE In this study, we investigated the applicability of MIF in serum samples as a biomarker in lung cancer. METHODS In a retrospective approach, we analyzed the sera of 79 patients with non-small-cell lung cancer (NSCLC) and 14 patients with small-cell lung cancer (SCLC) before the start of chemotherapy, as well as before the second and third chemotherapy cycle, respectively. Serum MIF levels were measured using a sandwich immunoassay with a sulfo-tag-labelled detection antibody, while pro-gastrin releasing peptide (proGRP) levels were determined with an enzyme-linked immunosorbent assay. RESULTS No difference in serum MIF levels between responders and non-responders to chemotherapy was observed at all time points, while proGRP levels were significantly lower in responders before the second chemotherapy cycle (p = 0.012). No differences in biomarker levels depending on the histopathological classification of NSCLC patients was found. Moreover, in ROC curve analyses MIF was not able to distinguish between responders and non-responders to therapy. proGRP could differentiate between responders and non-responders before the second chemotherapy cycle (p = 0.015) with sensitivities of 43% at 90% and 95% specificity, respectively. Likewise, proGRP yielded significantly longer survival times of patients with low proGRP concentrations before the second chemotherapy cycle (p = 0.015) in Kaplan-Meier analyses, yet MIF showed no significant differences in survival times at all time points. Comparison with the biomarkers CEA and CYFRA 21-1 in the same cohort showed that these established biomarkers clearly performed superior to MIF and proGRP. CONCLUSIONS From the present results, there is no indication that serum MIF may serve as a biomarker in prognosis and monitoring of response to therapy in lung cancer. Limitations of this study include its retrospective design, the inclusion of a larger NSCLC and a smaller SCLC subgroup, the classical chemotherapeutic treatment, the use of a non-diagnostic immunoassay (RUO-test) for MIF measurement and the lack of a validation cohort. Strengths of the study are its highly standardized procedures concerning sample collection, preanalytic treatment, measurements and quality control of the laboratory assays.
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Affiliation(s)
- Alexander Rupp
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Centre Munich, Munich, Germany
| | - Sophie Bahlmann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Nicolai Trimpop
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | | | - Stefan Holdenrieder
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Centre Munich, Munich, Germany
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
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20
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Jarmula J, Lee J, Lauko A, Rajappa P, Grabowski MM, Dhawan A, Chen P, Bucala R, Vogelbaum MA, Lathia JD. Macrophage migration inhibitory factor as a therapeutic target in neuro-oncology: A review. Neurooncol Adv 2024; 6:vdae142. [PMID: 39233830 PMCID: PMC11372298 DOI: 10.1093/noajnl/vdae142] [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] [Indexed: 09/06/2024] Open
Abstract
Primary central nervous system (CNS) tumors affect tens of thousands of patients each year, and there is a significant need for new treatments. Macrophage migration inhibitory factor (MIF) is a cytokine implicated in multiple tumorigenic processes such as cell proliferation, vascularization, and immune evasion and is therefore a promising therapeutic target in primary CNS tumors. There are several MIF-directed treatments available, including small-molecule inhibitors, peptide drugs, and monoclonal antibodies. However, only a small number of these drugs have been tested in preclinical models of primary CNS tumors, and even fewer have been studied in patients. Moreover, the brain has unique therapeutic requirements that further make effective targeting challenging. In this review, we summarize the latest functions of MIF in primary CNS tumor initiation and progression. We also discuss advances in MIF therapeutic development and ongoing preclinical studies and clinical trials. Finally, we discuss potential future MIF therapies and the strategies required for successful clinical translation.
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Affiliation(s)
- Jakub Jarmula
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Juyeun Lee
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Adam Lauko
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Prajwal Rajappa
- Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Matthew M Grabowski
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Andrew Dhawan
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Peiwen Chen
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Richard Bucala
- Section of Rheumatology, Allergy, and Immunology, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Michael A Vogelbaum
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Justin D Lathia
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA
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21
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Zhu Y, Sun Y, Shi Y, Ding Y, Liu C, Yang F, Chen F, Cao Y, Qin J. Construction of "Coral" SERS sensor for ultrasensitive and rapid detection of harmful component macrophage migration inhibitory factor in Platelet-rich Plasma. Biosens Bioelectron 2023; 242:115718. [PMID: 37801837 DOI: 10.1016/j.bios.2023.115718] [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: 09/06/2023] [Accepted: 09/28/2023] [Indexed: 10/08/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory factor produced by residual red blood cell lysis, which can significantly influence the curative effect of Platelet-rich plasma (PRP) therapy used for osteoarthritis (OA) treatment. In this study, we proposed a novel approach for detecting the concentration of MIF in PRP using a dopamine-coated antibody-Au (core)-Ag (shell)-SERS sensor, which enables ultrasensitive and rapid detection of MIF. The best experimental conditions have a detection limit of only 90.05 pg/mL and a good linear relationship between 1-5000 ng/mL. In 40 PRP samples collected from actual clinical patients, we detected MIF concentrations ranging from 2.0-3.6 ng/mL. This indicated that the Coral SERS sensor not only allows for results highly consistent with the traditional ELISA method, but also costs less ($0.40-$0.70), needs shorter testing time (integration time is only 10s), and consumes less PRP that can greatly improve the sample quality and maximize the curative effect in clinical applications for OA treatment with PRP.
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Affiliation(s)
- Yiran Zhu
- Department of Orthopedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, PR China
| | - Yang Sun
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, PR China
| | - Yang Shi
- School of Pharmacy, Nanjing Medical University, Nanjing, PR China
| | - Yan Ding
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, PR China
| | - Cheng Liu
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, PR China
| | - Fei Yang
- Department of Orthopedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, PR China
| | - Feng Chen
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, PR China.
| | - Yue Cao
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, PR China.
| | - Jian Qin
- Department of Orthopedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, PR China.
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22
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Chen G, Hu X, Huang Y, Xiang X, Pan S, Chen R, Xu X. Role of the immune system in liver transplantation and its implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e444. [PMID: 38098611 PMCID: PMC10719430 DOI: 10.1002/mco2.444] [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: 05/07/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/17/2023] Open
Abstract
Liver transplantation (LT) stands as the gold standard for treating end-stage liver disease and hepatocellular carcinoma, yet postoperative complications continue to impact survival rates. The liver's unique immune system, governed by a microenvironment of diverse immune cells, is disrupted during processes like ischemia-reperfusion injury posttransplantation, leading to immune imbalance, inflammation, and subsequent complications. In the posttransplantation period, immune cells within the liver collaboratively foster a tolerant environment, crucial for immune tolerance and liver regeneration. While clinical trials exploring cell therapy for LT complications exist, a comprehensive summary is lacking. This review provides an insight into the intricacies of the liver's immune microenvironment, with a specific focus on macrophages and T cells as primary immune players. Delving into the immunological dynamics at different stages of LT, we explore the disruptions after LT and subsequent immune responses. Focusing on immune cell targeting for treating liver transplant complications, we provide a comprehensive summary of ongoing clinical trials in this domain, especially cell therapies. Furthermore, we offer innovative treatment strategies that leverage the opportunities and prospects identified in the therapeutic landscape. This review seeks to advance our understanding of LT immunology and steer the development of precise therapies for postoperative complications.
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Affiliation(s)
- Guanrong Chen
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xin Hu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Yingchen Huang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xiaonan Xiang
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Sheng Pan
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiao Xu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
- Zhejiang Chinese Medical UniversityHangzhouChina
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23
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Zhang Y, Zheng L, Fang J, Ni K, Hu X, Ye L, Lai H, Yang T, Chen Z, He D. Macrophage migration inhibitory factor (MIF) promotes intervertebral disc degeneration through the NF-κB pathway, and the MIF inhibitor CPSI-1306 alleviates intervertebral disc degeneration in a mouse model. FASEB J 2023; 37:e23303. [PMID: 37983963 DOI: 10.1096/fj.202301441r] [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: 07/15/2023] [Revised: 10/07/2023] [Accepted: 10/26/2023] [Indexed: 11/22/2023]
Abstract
Lumbar intervertebral disc degeneration(IDD) is a prevalent inflammatory disease caused by many proinflammatory factors, such as TNF and IL-1β. Migration inhibitory factor (MIF) is an upstream inflammatory factor widely expressed in vivo that is associated with a variety of inflammatory diseases or malignant tumors and has potential therapeutic value in many diseases. We explored the role of MIF in intervertebral disc degeneration by regulating the content of exogenous MIF or the expression of MIF in cells. Upon inducing degeneration of nucleus pulposus (NP) cells with IL-1β, we found that the increase in intracellular and exogenous MIF promoted the catabolism induced by proinflammatory factors in NP cells, while silencing of the MIF gene alleviated the degeneration to some extent. In a mouse model, the intervertebral disc degeneration of MIF-KO mice was significantly less than that of wild-type mice. To explore the treatment of intervertebral disc degeneration, we selected the small-molecular MIF inhibitor CPSI-1306. CPSI-1306 had a therapeutic effect on intervertebral disc degeneration in the mouse model. In summary, we believe that MIF plays an important role in intervertebral disc degeneration and is a potential therapeutic target for the treatment of intervertebral disc degeneration.
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Affiliation(s)
- Yejin Zhang
- Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, China
| | - Lin Zheng
- Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
| | - Jiawei Fang
- Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, China
| | - Kainan Ni
- Department of Orthopaedics, The First People's Hospital of Fuyang, Hangzhou, China
| | - Xingyu Hu
- Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, China
| | - Lin Ye
- Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, China
| | - Hehuan Lai
- Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, China
| | - Tao Yang
- Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, China
| | - Zhenzhong Chen
- Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, China
| | - Dengwei He
- Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, China
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24
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Zaripova LN, Midgley A, Christmas SE, Beresford MW, Pain C, Baildam EM, Oldershaw RA. Mesenchymal Stem Cells in the Pathogenesis and Therapy of Autoimmune and Autoinflammatory Diseases. Int J Mol Sci 2023; 24:16040. [PMID: 38003230 PMCID: PMC10671211 DOI: 10.3390/ijms242216040] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 11/26/2023] Open
Abstract
Mesenchymal stem cells (MSCs) modulate immune responses and maintain self-tolerance. Their trophic activities and regenerative properties make them potential immunosuppressants for treating autoimmune and autoinflammatory diseases. MSCs are drawn to sites of injury and inflammation where they can both reduce inflammation and contribute to tissue regeneration. An increased understanding of the role of MSCs in the development and progression of autoimmune disorders has revealed that MSCs are passive targets in the inflammatory process, becoming impaired by it and exhibiting loss of immunomodulatory activity. MSCs have been considered as potential novel cell therapies for severe autoimmune and autoinflammatory diseases, which at present have only disease modifying rather than curative treatment options. MSCs are emerging as potential therapies for severe autoimmune and autoinflammatory diseases. Clinical application of MSCs in rare cases of severe disease in which other existing treatment modalities have failed, have demonstrated potential use in treating multiple diseases, including rheumatoid arthritis, systemic lupus erythematosus, myocardial infarction, liver cirrhosis, spinal cord injury, multiple sclerosis, and COVID-19 pneumonia. This review explores the biological mechanisms behind the role of MSCs in autoimmune and autoinflammatory diseases. It also covers their immunomodulatory capabilities, potential therapeutic applications, and the challenges and risks associated with MSC therapy.
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Affiliation(s)
- Lina N. Zaripova
- Institute of Fundamental and Applied Medicine, National Scientific Medical Center, 42 Abylai Khan Avenue, Astana 010000, Kazakhstan;
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
| | - Angela Midgley
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
| | - Stephen E. Christmas
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, Faculty of Health and Life Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby Street, Liverpool L69 7BE, UK;
| | - Michael W. Beresford
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
- Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK
| | - Clare Pain
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
- Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK
| | - Eileen M. Baildam
- Department of Paediatric Rheumatology, The Alexandra Hospital, Mill Lane, Cheadle SK8 2PX, UK;
| | - Rachel A. Oldershaw
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
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25
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Hawthorne IJ, Dunbar H, Tunstead C, Schorpp T, Weiss DJ, Enes SR, Dos Santos CC, Armstrong ME, Donnelly SC, English K. Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma. Mol Ther 2023; 31:3243-3258. [PMID: 37735872 PMCID: PMC10638061 DOI: 10.1016/j.ymthe.2023.09.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/28/2023] [Accepted: 09/14/2023] [Indexed: 09/23/2023] Open
Abstract
Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT7 mice but not in CATT5 or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT7 mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT6/7/8).
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Affiliation(s)
- Ian J Hawthorne
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Hazel Dunbar
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Courteney Tunstead
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Tamara Schorpp
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Daniel J Weiss
- Department of Medicine, 226 Health Sciences Research Facility, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
| | - Sara Rolandsson Enes
- Department of Experimental Medical Science, Faculty of Medicine, Lund University, 22100 Lund, Sweden
| | - Claudia C Dos Santos
- The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, 30 Bond Street, Toronto, ON, Canada; Institute of Medical Sciences and Interdepartmental Division of Critical Care, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | | | | | - Karen English
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.
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26
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Treasure K, Harris J, Williamson G. Exploring the anti-inflammatory activity of sulforaphane. Immunol Cell Biol 2023; 101:805-828. [PMID: 37650498 DOI: 10.1111/imcb.12686] [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: 03/20/2023] [Revised: 07/24/2023] [Accepted: 08/10/2023] [Indexed: 09/01/2023]
Abstract
Dysregulation of innate immune responses can result in chronic inflammatory conditions. Glucocorticoids, the current frontline therapy, are effective immunosuppressive drugs but come with a trade-off of cumulative and serious side effects. Therefore, alternative drug options with improved safety profiles are urgently needed. Sulforaphane, a phytochemical derived from plants of the brassica family, is a potent inducer of phase II detoxification enzymes via nuclear factor-erythroid factor 2-related factor 2 (NRF2) signaling. Moreover, a growing body of evidence suggests additional diverse anti-inflammatory properties of sulforaphane through interactions with mediators of key signaling pathways and inflammatory cytokines. Multiple studies support a role for sulforaphane as a negative regulator of nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) activation and subsequent cytokine release, inflammasome activation and direct regulation of the activity of macrophage migration inhibitory factor. Significantly, studies have also highlighted potential steroid-sparing activity for sulforaphane, suggesting that it may have potential as an adjunctive therapy for some inflammatory conditions. This review discusses published research on sulforaphane, including proposed mechanisms of action, and poses questions for future studies that might help progress our understanding of the potential clinical applications of this intriguing molecule.
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Affiliation(s)
- Katie Treasure
- Department of Nutrition, Dietetics and Food, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
- Victorian Heart Hospital, Monash University, Clayton, VIC, Australia
| | - James Harris
- Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Clayton, VIC, Australia
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| | - Gary Williamson
- Department of Nutrition, Dietetics and Food, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
- Victorian Heart Hospital, Monash University, Clayton, VIC, Australia
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27
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Townsend LK, Steinberg GR. AMPK and the Endocrine Control of Metabolism. Endocr Rev 2023; 44:910-933. [PMID: 37115289 DOI: 10.1210/endrev/bnad012] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/10/2023] [Accepted: 04/24/2023] [Indexed: 04/29/2023]
Abstract
Complex multicellular organisms require a coordinated response from multiple tissues to maintain whole-body homeostasis in the face of energetic stressors such as fasting, cold, and exercise. It is also essential that energy is stored efficiently with feeding and the chronic nutrient surplus that occurs with obesity. Mammals have adapted several endocrine signals that regulate metabolism in response to changes in nutrient availability and energy demand. These include hormones altered by fasting and refeeding including insulin, glucagon, glucagon-like peptide-1, catecholamines, ghrelin, and fibroblast growth factor 21; adipokines such as leptin and adiponectin; cell stress-induced cytokines like tumor necrosis factor alpha and growth differentiating factor 15, and lastly exerkines such as interleukin-6 and irisin. Over the last 2 decades, it has become apparent that many of these endocrine factors control metabolism by regulating the activity of the AMPK (adenosine monophosphate-activated protein kinase). AMPK is a master regulator of nutrient homeostasis, phosphorylating over 100 distinct substrates that are critical for controlling autophagy, carbohydrate, fatty acid, cholesterol, and protein metabolism. In this review, we discuss how AMPK integrates endocrine signals to maintain energy balance in response to diverse homeostatic challenges. We also present some considerations with respect to experimental design which should enhance reproducibility and the fidelity of the conclusions.
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Affiliation(s)
- Logan K Townsend
- Centre for Metabolism Obesity and Diabetes Research, Hamilton, ON L8S 4L8, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Gregory R Steinberg
- Centre for Metabolism Obesity and Diabetes Research, Hamilton, ON L8S 4L8, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada
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28
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Chen J, Guo W, Du P, Cui T, Yang Y, Wang Y, Kang P, Zhang Z, Wang Q, Ye Z, Liu L, Jian Z, Gao T, Bian H, Li S, Li C. MIF inhibition alleviates vitiligo progression by suppressing CD8 + T cell activation and proliferation. J Pathol 2023; 260:84-96. [PMID: 36852981 DOI: 10.1002/path.6073] [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: 10/03/2022] [Revised: 01/18/2023] [Accepted: 02/22/2023] [Indexed: 03/01/2023]
Abstract
In vitiligo, autoreactive CD8+ T cells have been established as the main culprit considering its pathogenic role in mediating epidermal melanocyte-specific destruction. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule that plays a central role in various immune processes including the activation and proliferation of T cells; but whether MIF is intertwined in vitiligo development and progression and its involvement in aberrantly activated CD8+ T cells remains ill-defined. In this study, we found that MIF was overabundant in vitiligo patients and a mouse model for human vitiligo. Additionally, inhibiting MIF ameliorated the disease progression in vitiligo mice, which manifested as less infiltration of CD8+ T cells and more retention of epidermal melanocytes in the tail skin. More importantly, in vitro experiments indicated that MIF-inhibition suppressed the activation and proliferation of CD8+ T cells from the lymph nodes of vitiligo mice, and the effect extended to CD8+ T cells in peripheral blood mononuclear cells of vitiligo patients. Finally, CD8+ T cells derived from MIF-inhibited vitiligo mice also exhibited an impaired capacity for activation and proliferation. Taken together, our results show that MIF might be clinically targetable in vitiligo treatment, and its inhibition might ameliorate vitiligo progression by suppressing autoreactive CD8+ T cell activation and proliferation. © 2023 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Jianru Chen
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Weinan Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Pengran Du
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Tingting Cui
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Yuqi Yang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Yinghan Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Pan Kang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Zhe Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Qi Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Zhubiao Ye
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Ling Liu
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Zhe Jian
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Tianwen Gao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Huijie Bian
- National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an, PR China
| | - Shuli Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
| | - Chunying Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
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Goretzki A, Zimmermann J, Rainer H, Lin YJ, Schülke S. Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment - Disease-Specific Findings (Part 1). Curr Allergy Asthma Rep 2023; 23:29-40. [PMID: 36441389 PMCID: PMC9832111 DOI: 10.1007/s11882-022-01057-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2022] [Indexed: 11/29/2022]
Abstract
PURPOSE OF REVIEW Recent high-level publications have shown an intricate connection between immune effector function and the metabolic state of the respective cells. In the last years, studies have begun analyzing the metabolic changes associated with allergies. As the first part of a two-article series, this review will briefly summarize the basics of immune metabolism and then focus on the recently published studies on metabolic changes observed in allergic patients. RECENT FINDINGS In the last 3 years, immune-metabolic research in allergology had a clear focus on asthma with some studies also reporting findings in food allergy and atopic dermatitis. Current results suggest asthma to be associated with a shift in cellular metabolism towards increased aerobic glycolysis (Warburg metabolism), while also displaying substantial changes in fatty acid- and amino acid metabolism (depending on investigated patient collective, asthma phenotype, and disease severity). Understanding immune-metabolic changes in allergies will allow us to (I) better understand allergic disease pathology and (II) modulate immune-metabolic pathways to improve allergy treatment.
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Affiliation(s)
- A. Goretzki
- Vice President’s Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany
| | - J. Zimmermann
- Vice President’s Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany
| | - H. Rainer
- Vice President’s Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany
| | - Y.-J. Lin
- Vice President’s Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany
| | - Stefan Schülke
- Vice President's Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225, Langen, Germany.
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Macrophage Migration Inhibitory Factor in Major Depressive Disorder: A Multilevel Pilot Study. Int J Mol Sci 2022; 23:ijms232415460. [PMID: 36555097 PMCID: PMC9779321 DOI: 10.3390/ijms232415460] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 11/30/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a controversially discussed inflammatory marker in major depressive disorder (MDD). While some studies show an association of high MIF protein levels with depression, animal models have yielded conflicting results. Thus, it remains elusive as to whether MIF plays an anti- or pro-depressive role. Therefore, we aimed to examine the potential of MIF at the genetic, expression and protein levels as a risk factor and biomarker to diagnose, monitor, or predict the course of MDD. Patients with a current major depressive episode (n = 66 with, and n = 63 without, prior medication) and remitted patients (n = 39) were compared with healthy controls (n = 61). Currently depressed patients provided a second blood sample after three weeks of therapy. Depression severity was assessed by self-evaluation and clinician rating scales. We genotyped for three MIF polymorphisms and analyzed peripheral MIF expression and serum levels. The absence of minor allele homozygous individuals in the large group of 96 female patients compared with 10-16% in female controls suggests a protective effect for MDD, which was not observed in the male group. There were no significant group differences of protein and expression levels, however, both showed predictive potential for the course of depression severity in some subgroups. While MIF protein levels, but not MIF expression, decreased during treatment, they were not associated with changes in depression severity. This project is the first to investigate three biological levels of MIF in depression. The data hint toward a genetic effect in women, but do not provide robust evidence for the utility of MIF as a biomarker for the diagnosis or monitoring of MDD. The observed predictive potential requires further analysis, emphasizing future attention to confounding factors such as sex and premedication.
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Wang Y, Lai Y, Fan X, Zhao Y. Macrophage migration inhibitory factor is vital for inflammatory properties and survival of peripheral blood leukocytes via enhancing mitochondrial function in Ctenopharyngodon idellus. FISH & SHELLFISH IMMUNOLOGY 2022; 131:518-526. [PMID: 36272522 DOI: 10.1016/j.fsi.2022.10.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/10/2022] [Accepted: 10/14/2022] [Indexed: 06/16/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic protein implicated in a broad spectrum of inflammatory and proliferative disorders. The gene sequence of grass carp (Ctenopharyngodon idella) was identified and the expression level of it was regulated by cadmium exposure in our previous study. To further clarify the immune-regulatory activity of grass carp MIF, MIF was over-expressed and interfered in grass carp peripheral blood leukocytes via transfection of plasmids pcDNA3.1-MIF-EGFP and pLKO.1-shRNA-EGFP-puro, respectively. Subsequently, survival, phagocytic capacity, mitochondrial function and cytokine production of the transfected leukocytes were assayed. The results shown that grass carp MIF was necessary for leukocyte survival, because it enhanced leukocyte viability and inhibited cell apoptosis, while MIF interference disrupted the cell viability and induced leukocyte apoptosis. The effect might benefit from improved mitochondrial function as evidenced by increased ATP production, which was due to maintained mitochondrial trans-membrane potential. In addition, MIF is essential for neutral red uptake into leukocyte, and it provoked chemokine monocyte chemotactic protein-1 (MCP-1), pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα), interleukin 1β (IL1β), interleukin 6 (IL6), interleukin 8 (IL8), and suppressed anti-inflammatory cytokine interleukin 10 (IL10) production. These results indicated that grass carp MIF played a vital role in regulating inflammatory properties and survival of peripheral blood leukocytes.
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Affiliation(s)
- Yilin Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Sichuan Province, College of Animal and Veterinary Science, Southwest Minzu University, Chengdu, 610041, PR China
| | - Yaling Lai
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Sichuan Province, College of Animal and Veterinary Science, Southwest Minzu University, Chengdu, 610041, PR China
| | - Xianyang Fan
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Sichuan Province, College of Animal and Veterinary Science, Southwest Minzu University, Chengdu, 610041, PR China
| | - Yanying Zhao
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Sichuan Province, College of Animal and Veterinary Science, Southwest Minzu University, Chengdu, 610041, PR China.
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Zan C, Yang B, Brandhofer M, El Bounkari O, Bernhagen J. D-dopachrome tautomerase in cardiovascular and inflammatory diseases-A new kid on the block or just another MIF? FASEB J 2022; 36:e22601. [PMID: 36269019 DOI: 10.1096/fj.202201213r] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 11/11/2022]
Abstract
Macrophage migration inhibitory factor (MIF) as well as its more recently described structural homolog D-dopachrome tautomerase (D-DT), now also termed MIF-2, are atypical cytokines and chemokines with key roles in host immunity. They also have an important pathogenic role in acute and chronic inflammatory conditions, cardiovascular diseases, lung diseases, adipose tissue inflammation, and cancer. Although our mechanistic understanding of MIF-2 is relatively limited compared to the extensive body of evidence available for MIF, emerging data suggests that MIF-2 is not only a functional phenocopy of MIF, but may have differential or even oppositional activities, depending on the disease and context. In this review, we summarize and discuss the similarities and differences between MIF and MIF-2, with a focus on their structures, receptors, signaling pathways, and their roles in diseases. While mainly covering the roles of the MIF homologs in cardiovascular, inflammatory, autoimmune, and metabolic diseases, we also discuss their involvement in cancer, sepsis, and chronic obstructive lung disease (COPD). A particular emphasis is laid upon potential mechanistic explanations for synergistic or cooperative activities of the MIF homologs in cancer, myocardial diseases, and COPD as opposed to emerging disparate or antagonistic activities in adipose tissue inflammation, metabolic diseases, and atherosclerosis. Lastly, we discuss potential future opportunities of jointly targeting MIF and MIF-2 in certain diseases, whereas precision targeting of only one homolog might be preferable in other conditions. Together, this article provides an update of the mechanisms and future therapeutic avenues of human MIF proteins with a focus on their emerging, surprisingly disparate activities, suggesting that MIF-2 displays a variety of activities that are distinct from those of MIF.
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Affiliation(s)
- Chunfang Zan
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Bishan Yang
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Markus Brandhofer
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Omar El Bounkari
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Jürgen Bernhagen
- Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilian-University (LMU), Munich, Germany.,Deutsches Zentrum für Herz-Kreislauferkrankungen (DZHK), Munich Heart Alliance, Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Impact of Steroid on Macrophage Migration Inhibitory Factor During and After Cardiopulmonary Bypass. ASAIO J 2022; 69:391-395. [PMID: 36730972 DOI: 10.1097/mat.0000000000001836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released in response to glucocorticoids, which counter-regulates the effects of glucocorticoids. This study was performed to determine the impact of steroids on the expression of MIF and other pro- and anti-inflammatory cytokines during and after cardiopulmonary bypass (CPB). Twenty adult patients (10 men, 64 ± 8 years old) who underwent elective cardiac surgery by CPB were given either 2000 mg (group-H, n = 10) or 500 mg of methylprednisolone (group-L, n = 10) during CPB. The serum concentrations of MIF, interleukin (IL)-1β, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α) were measured at eight time points until 36 hours after skin closure. The early postoperative course was uneventful for all patients. There were no significant differences in duration of operation, CPB, or aortic cross-clamping (AXC) between the two groups. MIF and IL-10 levels peaked just after the conclusion of CPB and decreased gradually thereafter. IL-1β, IL-8, and TNF-α were undetectable throughout the study period. There were no significant differences in MIF or IL-10 levels between the two groups. Peak levels of MIF in all patients were significantly correlated with the duration of CPB and AXC, whereas no such correlation was observed for IL-10. MIF or IL-10 levels were significantly elevated during and after CPB, but there were no differences between the two doses of steroid administration. Both steroid doses sufficiently suppressed proinflammatory cytokines. MIF better reflected the invasiveness of the operation than IL-10.
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Jia Q, Hao RJL, Lu XJ, Sun SQ, Shao JJ, Su X, Huang QF. Identification of hub biomarkers and immune cell infiltration characteristics of polymyositis by bioinformatics analysis. Front Immunol 2022; 13:1002500. [PMID: 36225941 PMCID: PMC9548705 DOI: 10.3389/fimmu.2022.1002500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/09/2022] [Indexed: 11/13/2022] Open
Abstract
Background Polymyositis (PM) is an acquirable muscle disease with proximal muscle involvement of the extremities as the main manifestation; it is a category of idiopathic inflammatory myopathy. This study aimed to identify the key biomarkers of PM, while elucidating PM-associated immune cell infiltration and immune-related pathways. Methods The gene microarray data related to PM were downloaded from the Gene Expression Omnibus database. The analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks were performed on differentially expressed genes (DEGs). The hub genes of PM were identified using weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) algorithm, and the diagnostic accuracy of hub markers for PM was assessed using the receiver operating characteristic curve. In addition, the level of infiltration of 28 immune cells in PM and their interrelationship with hub genes were analyzed using single-sample GSEA. Results A total of 420 DEGs were identified. The biological functions and signaling pathways closely associated with PM were inflammatory and immune processes. A series of four expression modules were obtained by WGCNA analysis, with the turquoise module having the highest correlation with PM; 196 crossover genes were obtained by combining DEGs. Subsequently, six hub genes were finally identified as the potential biomarkers of PM using LASSO algorithm and validation set verification analysis. In the immune cell infiltration analysis, the infiltration of T lymphocytes and subpopulations, dendritic cells, macrophages, and natural killer cells was more significant in the PM. Conclusion We identified the hub genes closely related to PM using WGCNA combined with LASSO algorithm, which helped clarify the molecular mechanism of PM development and might have great significance for finding new immunotherapeutic targets, and disease prevention and treatment.
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Affiliation(s)
- Qi Jia
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Rui-Jin-Lin Hao
- Medical School of Nantong University, Nantong, China
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiao-Jian Lu
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Shu-Qing Sun
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Jun-Jie Shao
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Xing Su
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
- *Correspondence: Qing-Feng Huang, ; Xing Su,
| | - Qing-Feng Huang
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
- *Correspondence: Qing-Feng Huang, ; Xing Su,
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Chen S, Li A, Wu J, Huang Y, Zou T, Tailaiti T, Wang J. Dexmedetomidine reduces myocardial ischemia-reperfusion injury in young mice through MIF/AMPK/GLUT4 axis. BMC Anesthesiol 2022; 22:289. [PMID: 36104681 PMCID: PMC9472426 DOI: 10.1186/s12871-022-01825-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 08/30/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Reperfusion of ischemic tissue has adverse impact on the myocardium. Dexmedetomidine (Dex) is a α2-adrenergic receptor (α2-AR) agonist with sedative and analgesic effects. Macrophage migration inhibition factor (MIF) is a pressure-regulating cytokine and is responsible for inflammatory and immune diseases. This study aims to reveal the consequences of Dex on myocardial ischemia-reperfusion injury (IRI) in young mice. METHODS Fifty mice were raised and examined. At the end of the experiment, all mice were euthanized. The anterior descending department of the left coronary artery in mice was under ischemia for 60 min, then the ligation line was released and reperfused for 120 min to establish the IRI model. Mice were randomly divided into Sham, control, treatment using 4,5-dihydro-3-(4-hydroxyphenyl)-5-isoxazoleacetic acid (ISO-1), Dex treatment, and Dex combined ISO-1 treatment groups. Interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) and ATP levels were recorded. The expressions of MIF, P-adenosine monophosphate-activated kinase α (AMPKα), glucose transporter (GLUT)4, Bax and Bcl-2 were detected by Western Blot (WB). Hematoxylin and Eosin (H&E) staining was used to study cell morphology. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. Echocardiography was carried out at the end of reperfusion, and the infarct size was calculated by Electron microscopy. RESULTS I/R + Dex group showed significantly increased IL-6 and TNF-α levels and reduced myocardial cell necrosis and apoptosis. H&E staining showed alleviated myocardial disorder, myocardial cell swelling, myocardial fiber fracture, and inflammatory cell infiltration in I/R + Dex group. Myocardial cell necrosis and apoptosis were significantly reduced in I/R + Dex group. ATP level in myocardial tissue of mice in I/R group was substantially decreased, while that in Dex group was increased. WB results showed that MIF, P-AMPK α, GLUT4 and Bcl-2 levels were increased and Bax levels were decreased in I/R + Dex group. CONCLUSION Dex may exert myocardial protection in young mice through MIF/AMPK/GLUT4 axis.
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Affiliation(s)
- Siyu Chen
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No.137, Liyushan Road, Xinshi District, Urumqi, Xinjiang, 830054, Uygur Autonomous Region, China
| | - Aimei Li
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No.137, Liyushan Road, Xinshi District, Urumqi, Xinjiang, 830054, Uygur Autonomous Region, China
| | - Jianjiang Wu
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No.137, Liyushan Road, Xinshi District, Urumqi, Xinjiang, 830054, Uygur Autonomous Region, China
| | - Yidan Huang
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No.137, Liyushan Road, Xinshi District, Urumqi, Xinjiang, 830054, Uygur Autonomous Region, China
| | - Tiantian Zou
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No.137, Liyushan Road, Xinshi District, Urumqi, Xinjiang, 830054, Uygur Autonomous Region, China
| | - Taiwangu Tailaiti
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No.137, Liyushan Road, Xinshi District, Urumqi, Xinjiang, 830054, Uygur Autonomous Region, China
| | - Jiang Wang
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, No.137, Liyushan Road, Xinshi District, Urumqi, Xinjiang, 830054, Uygur Autonomous Region, China.
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Thiele M, Donnelly SC, Mitchell RA. OxMIF: a druggable isoform of macrophage migration inhibitory factor in cancer and inflammatory diseases. J Immunother Cancer 2022; 10:e005475. [PMID: 36180072 PMCID: PMC9528626 DOI: 10.1136/jitc-2022-005475] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2022] [Indexed: 11/04/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with a pleiotropic spectrum of biological functions implicated in the pathogenesis of cancer and inflammatory diseases. MIF is constitutively present in several cell types and non-lymphoid tissues and is secreted after acute stress or inflammation. MIF triggers the release of proinflammatory cytokines, overrides the anti-inflammatory effects of glucocorticoids, and exerts chemokine function, resulting in increased migration and recruitment of leukocytes into inflamed tissue. Despite this, MIF is a challenging target for therapeutic intervention because of its ubiquitous nature and presence in the circulation and tissue of healthy individuals. Oxidized MIF (oxMIF) is an immunologically distinct disease-related structural isoform found in the plasma and tissues of patients with inflammatory diseases and in solid tumor tissues. MIF converts to oxMIF in an oxidizing, inflammatory environment. This review discusses the biology and activity of MIF and the potential for autoimmune disease and cancer modification by targeting oxMIF. Anti-oxMIF antibodies reduce cancer cell invasion/migration, angiogenesis, proinflammatory cytokine production, and ERK and AKT activation. Anti-oxMIF antibodies also elicit apoptosis and alter immune cell function and/or migration. When co-administered with a glucocorticoid, anti-oxMIF antibodies produced a synergistic response in inflammatory models. Anti-oxMIF antibodies therefore counterregulate biological activities attributed to MIF. oxMIF expression has been observed in inflammatory diseases (eg, sepsis, psoriasis, asthma, inflammatory bowel disease, and systemic lupus erythematosus) and oxMIF has been detected in ovarian, colorectal, lung, and pancreatic cancers. In contrast to MIF, oxMIF is specifically detected in plasma and/or tissues of diseased patients, but not in healthy individuals. Therefore, as a druggable isoform of MIF, oxMIF represents a potential new therapeutic target in inflammatory diseases and cancer. Fully human, monoclonal anti-oxMIF antibodies have been shown to selectively bind oxMIF in preclinical and phase I studies; however, additional clinical assessments are necessary to validate their use as either a monotherapy or in combination with standard-of-care regimens (ie, immunomodulatory agents/checkpoint inhibitors, anti-angiogenic drugs, chemotherapeutics, and glucocorticoids).
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Affiliation(s)
- Michael Thiele
- Biology Research, OncoOne Research & Development GmbH, Vienna, Austria
| | - Seamas C Donnelly
- Department of Medicine, Tallaght University Hospital & Trinity College Dublin, Dublin, Ireland
| | - Robert A Mitchell
- Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky, USA
- Department of Surgery, J.G. Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
- Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA
- Division of Immunotherapy, Department of Surgery, University of Louisville, Louisville, Kentucky, USA
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Harris J, Borg NA. The multifaceted roles of NLRP3-modulating proteins in virus infection. Front Immunol 2022; 13:987453. [PMID: 36110852 PMCID: PMC9468583 DOI: 10.3389/fimmu.2022.987453] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/11/2022] [Indexed: 12/14/2022] Open
Abstract
The innate immune response to viruses is critical for the correct establishment of protective adaptive immunity. Amongst the many pathways involved, the NLRP3 [nucleotide-binding oligomerisation domain (NOD)-like receptor protein 3 (NLRP3)] inflammasome has received considerable attention, particularly in the context of immunity and pathogenesis during infection with influenza A (IAV) and SARS-CoV-2, the causative agent of COVID-19. Activation of the NLRP3 inflammasome results in the secretion of the proinflammatory cytokines IL-1β and IL-18, commonly coupled with pyroptotic cell death. While this mechanism is protective and key to host defense, aberrant NLRP3 inflammasome activation causes a hyperinflammatory response and excessive release of cytokines, both locally and systemically. Here, we discuss key molecules in the NLRP3 pathway that have also been shown to have significant roles in innate and adaptive immunity to viruses, including DEAD box helicase X-linked (DDX3X), vimentin and macrophage migration inhibitory factor (MIF). We also discuss the clinical opportunities to suppress NLRP3-mediated inflammation and reduce disease severity.
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Affiliation(s)
- James Harris
- Cell Biology Assays Team, Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Clayton, VIC, Australia
- Centre for Inflammatory diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
| | - Natalie A. Borg
- Immunity and Immune Evasion Laboratory, Chronic Infectious and Inflammatory Diseases Research, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
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Zhang Z, Hu X, Diao Q, Zhang P, Wu Y, Cao Z, Zhou Y, Liu C, Sun Y. Macrophage migration inhibitory factor (MIF) of golden pompano (Trachinotus ovatus) is involved in the antibacterial immune response. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2022; 133:104445. [PMID: 35588935 DOI: 10.1016/j.dci.2022.104445] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/07/2022] [Accepted: 05/09/2022] [Indexed: 06/15/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with a unique structure involved in immune regulation and inflammation. In the present study, we identified a MIF from Trachinotus ovatus (golden pompano) and analyzed its function. TroMIF shares high homology (58.26%-94.78%) with the other known MIF sequences of vertebrates. TroMIF is most closely related to large yellow croaker (Larimichthys crocea). The expression of TroMIF was most abundant in the liver and head kidney, and was significantly up-regulated after Edwardsiella tarda infection. The subcellular localization of TroMIF was mostly distributed in the cytoplasm. In vitro results revealed that the recombinant protein rTroMIF could inhibit the migration of head kidney lymphocytes (HKLs) and macrophages (HKMs) and enhance the phagocytic activity of HKMs. As a pro-inflammatory cytokine, rTroMIF could increase the expression levels of some pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), IL-6, IL-8, and interferon-gamma (IFN-γ) and decrease the expression of IL-10. The rTroMIF was proved to have enzymatic redox activity in vitro. Furthermore, overexpression of TroMIF in the head kidney cell line of golden pompano could significantly enhance its ability to resist E. tarda infection from 1 h to 4 h. The knockdown of TroMIF expression induced a significant increase in the number of bacteria after E. tarda infection at 1, 2, and 4 hpi. Our results suggest that TroMIF is an essential effector of the innate immune system and plays a pivotal role in antibacterial immunity.
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Affiliation(s)
- Zhengshi Zhang
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, PR China; Hainan Provincial Key Laboratory for Tropical Hydrobiology and Biotechnology, College of Marine Science, Hainan University, PR China
| | - Xiucong Hu
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, PR China
| | - Qianying Diao
- Hainan Provincial Key Laboratory for Tropical Hydrobiology and Biotechnology, College of Marine Science, Hainan University, PR China
| | - Panpan Zhang
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, PR China; Hainan Provincial Key Laboratory for Tropical Hydrobiology and Biotechnology, College of Marine Science, Hainan University, PR China
| | - Ying Wu
- Hainan Provincial Key Laboratory for Tropical Hydrobiology and Biotechnology, College of Marine Science, Hainan University, PR China
| | - Zhenjie Cao
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, PR China
| | - Yongcan Zhou
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, PR China; Hainan Provincial Key Laboratory for Tropical Hydrobiology and Biotechnology, College of Marine Science, Hainan University, PR China
| | - Chunsheng Liu
- Hainan Provincial Key Laboratory for Tropical Hydrobiology and Biotechnology, College of Marine Science, Hainan University, PR China
| | - Yun Sun
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, PR China; Hainan Provincial Key Laboratory for Tropical Hydrobiology and Biotechnology, College of Marine Science, Hainan University, PR China.
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Ni L, Jing S, Zhu L, Yang X, Wang X, Tu S. The Immune Change of the Lung and Bowel in an Ulcerative Colitis Rat Model and the Protective Effect of Sodium Houttuyfonate Combined With Matrine. Front Immunol 2022; 13:888918. [PMID: 35844499 PMCID: PMC9280623 DOI: 10.3389/fimmu.2022.888918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/30/2022] [Indexed: 01/19/2023] Open
Abstract
Objective To explore the immune change of lung injury of Ulcerative colitis (UC) by observing the changes of inherent immunity and adaptive immunity of the lung and bowel in UC rat models after the treatment of Sodium Houttuyfonate combined with Matrine. Method UC rat models were established with the mucous membrane of colon allergize combined with TNBS-alcohol enteroclysis for 1 week and 5 weeks. 1-week experimental rats were divided into normal group and model group, 5/each group. 5-weeks experimental rats were divided into normal group, model group, Sodium Houttuyfonate (2.9mg/ml) combined with Matrine (1.47mg/ml), and positive control sulfasalazine (10mg/ml), 5/each group. All rats were administered by gavage for 5 weeks. The histopathological and fibrotic changes in the lung and bowel were observed, and the expressions of Tumor Necrosis Factor (TNF)- α, interleukin (IL)-8 in the lung, bowel, and serum were detected by radio-immunity and immunohistochemistry, and the mRNA expressions of Toll-like receptor (TLR)-4, nuclear factor kappa (NF-κB), Macrophage migration inhibitory factor (MIF), Mucosal addressing cell adhesion molecule-1 (MadCAM1) and Pulmonary surfactant protein-A (SP-A) in the lung and bowel were detected by Real time-PCR. Result Compared with the normal group, the model rats had significant histopathological and fibrotic changes both in the lung and bowel, and all treatment groups were improved. After treatment, TLR4, IL-8, MIF, and TNF-α in the lung decreased (P<0.05); NF-KB, IL-8, and MIF in the bowel increased (P<0.05); MadCAM1 both in lung and bowel decreased (P<0.05); SP-A decreased in bowel and increased in the lung (P<0.05). Conclusion The cause of lung injury in this model was found to be related to inherent immunity and adaptive immunity, while the cause of bowel injury in this model was found to be mainly related to adaptive immunity. Sodium Houttuyfonate combined with Matrine could improve bowel and lung injury.
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Affiliation(s)
- Lulu Ni
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Shan Jing
- Department of Internal Medicine of Traditional Chinese Medicine (TCM), Nantong Hospital, Nantong, China
| | - Li Zhu
- Department of Internal Medicine of Traditional Chinese Medicine (TCM), Dong- zhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xue Yang
- Department of Internal Medicine of Traditional Chinese Medicine (TCM), Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Xinyue Wang
- Department of Internal Medicine of Traditional Chinese Medicine (TCM), Dong- zhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Su Tu
- Department of Emergency, the Affiliated Wuxi NO 2 People’s Hospital of Nanjing Medical University, Wuxi, China
- *Correspondence: Su Tu,
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Hassan MH, Abuhamdah S, Elsadek BEM, Abdelwahab A, Abd-Elhamid TH, Fayed HM, Abbass A, Abdallah AAM, Mohamed M, Abd-Elmagid WM. Expression Patterns of Macrophage Migration Inhibitory Factor and Its Gene Variants (MIF-173 G˃C) in Verruca Vulgaris. Clin Cosmet Investig Dermatol 2022; 15:1073-1085. [PMID: 35712358 PMCID: PMC9196281 DOI: 10.2147/ccid.s363916] [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: 03/01/2022] [Accepted: 05/26/2022] [Indexed: 11/23/2022]
Abstract
Introduction Verruca vulgaris is a benign hyperkeratotic proliferation of the epidermis. Few studies look at the differences in serum and tissue macrophage migration inhibitory factor (MIF) levels in verruca vulgaris, as well as its gene polymorphisms that have yet to be explored. The current study provided in-depth evaluation of MIF in serum and tissues of patients with verruca vulgaris, and establishes for the first time the possible association of MIF gene polymorphisms with common warts. Methods This case-control study included 50 patients who were diagnosed clinically as common warts in comparison with 50 age and sex-matched controls. Clinical examination was done on all included cases. Serum MIF was measured using enzyme-linked immunosorbent assay (ELISA), while its tissue expression was analyzed using Western blotting and immunohistochemical techniques for the included participants. Analysis of MIF-173 G˃C single nucleotide polymorphism was performed by polymerase chain reaction (PCR) using restriction fragment length polymorphism (RFLP) technique. Results The overall results revealed significantly lower MIF tissue expression in lesional and perilesional skin biopsies from cases compared to the controls using Western blot and immunohistochemical analysis. Yet, the difference in the serum MIF levels between cases and controls was not significant (p ˃ 0.05). GC genotype of the studied MIF rs755622 G>C SNP could be considered as a protective genetic factor against the occurrence of verruca vulgaris among Egyptians with OR (95% CI) equal 0.444 (0.199-0.989). Conclusion MIF and its genetic variants are thought to play a pathogenic role in verruca vulgaris development and recurrence.
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Affiliation(s)
- Mohammed H Hassan
- Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, 83523, Egypt
| | - Sawsan Abuhamdah
- College of Pharmacy, Al Ain University, Abu Dhabi, United Arab Emirates.,Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, Amman, Jordan
| | - Bakheet E M Elsadek
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Ashraf Abdelwahab
- Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Tarek Hamdy Abd-Elhamid
- Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Hanan M Fayed
- Department of Chemical and Clinical Pathology, Faculty of Medicine, South Valley University, Qena, 83523, Egypt
| | - Amany Abbass
- Department of Chemical and Clinical Pathology, Faculty of Medicine, Sohag University, Sohag, Egypt
| | | | - Marwa Mohamed
- Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Wafaa Mohamed Abd-Elmagid
- Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt
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Park H, Kam TI, Peng H, Chou SC, Mehrabani-Tabari AA, Song JJ, Yin X, Karuppagounder SS, Umanah GK, Rao AVS, Choi Y, Aggarwal A, Chang S, Kim H, Byun J, Liu JO, Dawson TM, Dawson VL. PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease. Cell 2022; 185:1943-1959.e21. [PMID: 35545089 DOI: 10.1016/j.cell.2022.04.020] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 02/14/2022] [Accepted: 04/12/2022] [Indexed: 10/18/2022]
Abstract
Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.
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Affiliation(s)
- Hyejin Park
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Tae-In Kam
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Hanjing Peng
- Department of Pharmacology and Molecular Sciences and SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Shih-Ching Chou
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Amir A Mehrabani-Tabari
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jae-Jin Song
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Xiling Yin
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Senthilkumar S Karuppagounder
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - George K Umanah
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - A V Subba Rao
- Department of Pharmacology and Molecular Sciences and SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - YuRee Choi
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Akanksha Aggarwal
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Sohyun Chang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Hyunhee Kim
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jiyoung Byun
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jun O Liu
- Department of Pharmacology and Molecular Sciences and SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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Patel NM, Yamada N, Oliveira FRMB, Stiehler L, Zechendorf E, Hinkelmann D, Kraemer S, Stoppe C, Collino M, Collotta D, Alves GF, Ramos HP, Sordi R, Marzi I, Relja B, Marx G, Martin L, Thiemermann C. Inhibition of Macrophage Migration Inhibitory Factor Activity Attenuates Haemorrhagic Shock-Induced Multiple Organ Dysfunction in Rats. Front Immunol 2022; 13:886421. [PMID: 35464452 PMCID: PMC9019168 DOI: 10.3389/fimmu.2022.886421] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/14/2022] [Indexed: 12/13/2022] Open
Abstract
Objective The aim of this study was to investigate (a) macrophage migration inhibitory factor (MIF) levels in polytrauma patients and rats after haemorrhagic shock (HS), (b) the potential of the MIF inhibitor ISO-1 to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) HS rat models and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in HS. Background The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. MIF is a pleiotropic cytokine which can modulate the inflammatory response, however, its role in trauma is unknown. Methods The MIF levels in plasma of polytrauma patients and serum of rats with HS were measured by ELISA. Acute HS rat models were performed to determine the influence of ISO-1 on MODS. The activation of NF-κB and NLRP3 pathways were analysed by western blot in the kidney and liver. Results We demonstrated that (a) MIF levels are increased in polytrauma patients on arrival to the emergency room and in rats after HS, (b) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (c) treatment of HS-rats with ISO-1 attenuated the organ injury and dysfunction in acute HS models and (d) reduced the activation of NF-κB and NLRP3 pathways in the kidney and liver. Conclusion Our results point to a role of MIF in the pathophysiology of trauma-induced organ injury and dysfunction and indicate that MIF inhibitors may be used as a potential therapeutic approach for MODS after trauma and/or haemorrhage.
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Affiliation(s)
- Nikita M Patel
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Noriaki Yamada
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.,Gifu University Graduate School of Medicine, Department of Emergency and Disaster Medicine Gifu University Hospital Advanced Critical Care Center, Gifu, Japan
| | - Filipe R M B Oliveira
- Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Lara Stiehler
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.,Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Elisabeth Zechendorf
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Daniel Hinkelmann
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Sandra Kraemer
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Stoppe
- Department of Anesthesiology & Intensive Care Medicine, University Hospital Würzburg, Würzburg, Germany
| | - Massimo Collino
- Department of Neurosciences "Rita Levi Montalcini", University of Turin, Turin, Italy
| | - Debora Collotta
- Department of Neurosciences "Rita Levi Montalcini", University of Turin, Turin, Italy
| | | | - Hanna Pillmann Ramos
- Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Regina Sordi
- Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Ingo Marzi
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - Borna Relja
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.,Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg, Germany
| | - Gernot Marx
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Lukas Martin
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.,Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Christoph Thiemermann
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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Stijlemans B, Schoovaerts M, De Baetselier P, Magez S, De Trez C. The Role of MIF and IL-10 as Molecular Yin-Yang in the Modulation of the Host Immune Microenvironment During Infections: African Trypanosome Infections as a Paradigm. Front Immunol 2022; 13:865395. [PMID: 35464430 PMCID: PMC9022210 DOI: 10.3389/fimmu.2022.865395] [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: 01/29/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
African trypanosomes are extracellular flagellated unicellular protozoan parasites transmitted by tsetse flies and causing Sleeping Sickness disease in humans and Nagana disease in cattle and other livestock. These diseases are usually characterized by the development of a fatal chronic inflammatory disease if left untreated. During African trypanosome infection and many other infectious diseases, the immune response is mediating a see-saw balance between effective/protective immunity and excessive infection-induced inflammation that can cause collateral tissue damage. African trypanosomes are known to trigger a strong type I pro-inflammatory response, which contributes to peak parasitaemia control, but this can culminate into the development of immunopathologies, such as anaemia and liver injury, if not tightly controlled. In this context, the macrophage migration inhibitory factor (MIF) and the interleukin-10 (IL-10) cytokines may operate as a molecular “Yin-Yang” in the modulation of the host immune microenvironment during African trypanosome infection, and possibly other infectious diseases. MIF is a pleiotropic pro-inflammatory cytokine and critical upstream mediator of immune and inflammatory responses, associated with exaggerated inflammation and immunopathology. For example, it plays a crucial role in the pro-inflammatory response against African trypanosomes and other pathogens, thereby promoting the development of immunopathologies. On the other hand, IL-10 is an anti-inflammatory cytokine, acting as a master regulator of inflammation during both African trypanosomiasis and other diseases. IL-10 is crucial to counteract the strong MIF-induced pro-inflammatory response, leading to pathology control. Hence, novel strategies capable of blocking MIF and/or promoting IL-10 receptor signaling pathways, could potentially be used as therapy to counteract immunopathology development during African trypanosome infection, as well as during other infectious conditions. Together, this review aims at summarizing the current knowledge on the opposite immunopathological molecular “Yin-Yang” switch roles of MIF and IL-10 in the modulation of the host immune microenvironment during infection, and more particularly during African trypanosomiasis as a paradigm.
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Affiliation(s)
- Benoit Stijlemans
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Myeloid Cell Immunology Laboratory, Vlaams Instituut voor Biotechnologie (VIB) Centre for Inflammation Research, Brussels, Belgium
| | - Maxime Schoovaerts
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Patrick De Baetselier
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Myeloid Cell Immunology Laboratory, Vlaams Instituut voor Biotechnologie (VIB) Centre for Inflammation Research, Brussels, Belgium
| | - Stefan Magez
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Laboratory of Biomedical Research, Ghent University Global Campus, Incheon, South Korea
| | - Carl De Trez
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
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Skeens E, Gadzuk-Shea M, Shah D, Bhandari V, Schweppe DK, Berlow RB, Lisi GP. Redox-dependent structure and dynamics of macrophage migration inhibitory factor reveal sites of latent allostery. Structure 2022; 30:840-850.e6. [PMID: 35381187 DOI: 10.1016/j.str.2022.03.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/20/2022] [Accepted: 03/09/2022] [Indexed: 01/01/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is a multifunctional immunoregulatory protein that is a key player in the innate immune response. Given its overexpression at sites of inflammation and in diseases marked by increasingly oxidative environments, a comprehensive understanding of how cellular redox conditions impact the structure and function of MIF is necessary. We used NMR spectroscopy and mass spectrometry to investigate biophysical signatures of MIF under varied solution redox conditions. Our results indicate that the MIF structure is modified and becomes increasingly dynamic in an oxidative environment, which may be a means to alter the MIF conformation and functional response in a redox-dependent manner. We identified latent allosteric sites within MIF through mutational analysis of redox-sensitive residues, revealing that a loss of redox-responsive residues attenuates CD74 receptor activation. Leveraging sites of redox sensitivity as targets for structure-based drug design therefore reveals an avenue to modulate MIF function in its "disease state."
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Affiliation(s)
- Erin Skeens
- Department of Molecular Biology, Cell Biology, & Biochemistry, Brown University, Providence, RI 02903, USA
| | - Meagan Gadzuk-Shea
- Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
| | - Dilip Shah
- Section of Neonatology, Department of Pediatrics, Cooper University Hospital, Camden, NJ 08103, USA
| | - Vineet Bhandari
- Section of Neonatology, Department of Pediatrics, Cooper University Hospital, Camden, NJ 08103, USA
| | - Devin K Schweppe
- Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
| | - Rebecca B Berlow
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - George P Lisi
- Department of Molecular Biology, Cell Biology, & Biochemistry, Brown University, Providence, RI 02903, USA.
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Nagai K, Goto Y. Parasitomimetics: Can We Utilize Parasite-Derived Immunomodulatory Molecules for Interventions to Immunological Disorders? Front Immunol 2022; 13:824695. [PMID: 35386686 PMCID: PMC8977410 DOI: 10.3389/fimmu.2022.824695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/28/2022] [Indexed: 11/17/2022] Open
Abstract
Because our immune system has ability to expel microorganisms invading our body, parasites need evolution to maintain their symbiosis with the hosts. One such strategy of the parasites is to manipulate host immunity by producing immunomodulatory molecules and the ability of parasites to regulate host immunity has long been a target of research. Parasites can not only manipulate host immune response specific to them, but also influence the host's entire immune system. Such ability of the parasites may sometimes bring benefit to the hosts as many studies have indicated the "hygiene hypothesis" that a decreased opportunity of parasitic infections is associated with an increased incidence of allergy and autoimmune diseases. In other words, elucidating the mechanisms of parasites to regulate host immunity could be applied not only to resolution of parasitic infections but also to treatment of non-parasitic immunological disorders. In this review, we show how much progress has been made in the research on immunomodulation of host immunity by parasites. Here, we define the word 'parasitomimetics' as emulation of parasites' immunomodulatory systems to solve immunological problems in humans and discuss potential applications of parasite-derived molecules to other diseases.
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Affiliation(s)
| | - Yasuyuki Goto
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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Vesce F, Battisti C, Crudo M. The Inflammatory Cytokine Imbalance for Miscarriage, Pregnancy Loss and COVID-19 Pneumonia. Front Immunol 2022; 13:861245. [PMID: 35359975 PMCID: PMC8961687 DOI: 10.3389/fimmu.2022.861245] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 02/17/2022] [Indexed: 12/27/2022] Open
Abstract
Pregnancy can be defined a vascular event upon endocrine control. In the human hemo-chorial placentation the chorionic villi penetrate the wall of the uterine spiral arteries, to provide increasing amounts of nutrients and oxygen for optimal fetal growth. In any physiological pregnancy the natural maternal response is of a Th1 inflammatory type, aimed at avoiding blood loss through the arteriolar wall openings. The control of the vascular function, during gestation as in any other condition, is achieved through the action of two main types of prostanoids: prostaglandin E2 and thromboxane on the one hand (for vasoconstriction and coagulation), prostacyclin on the other (for vasodilation and blood fluidification). The control of the maternal immune response is upon the responsibility of the fetus itself. Indeed, the chorionic villi are able to counteract the natural maternal response, thus changing the inflammatory Th1 type into the anti-inflammatory Th2. Clinical and experimental research in the past half century address to inflammation as the leading cause of abortion, pregnancy loss, premature delivery and related pulmonary, cerebral, intestinal fetal syndromes. Increased level of Interleukin 6, Interleukin 1-beta, Tumor Necrosis Factor-alfa, Interferon-gamma, are some among the well-known markers of gestational inflammation. On the other side, COVID-19 pneumonia is a result of extensive inflammation induced by viral replication within the cells of the respiratory tract. As it may happen in the uterine arteries in the absence of an effective fetal control, viral pneumonia triggers pulmonary vascular coagulation. The cytokines involved in the process are the same as those in gestational inflammation. As the fetus breathes throughout the placenta, fetal death from placental thrombosis is similar to adult death from pulmonary thrombosis. Preventing and counteracting inflammation is mandatory in both conditions. The most relevant literature dealing with the above-mentioned concepts is reviewed in the present article.
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Affiliation(s)
- Fortunato Vesce
- OB & Gyn Complex Unit, Arcispedale Sant’Anna – Ferrara University, Ferrara, Italy
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Sumaiya K, Natarajaseenivasan K. Macrophage migration inhibitory factor gene promoter polymorphism (−173G/C SNP) determines host susceptibility and severity of leptospirosis. Microb Pathog 2022; 164:105445. [DOI: 10.1016/j.micpath.2022.105445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 10/19/2022]
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The Role of Cytokines in Nephrotic Syndrome. Mediators Inflamm 2022; 2022:6499668. [PMID: 35185384 PMCID: PMC8849808 DOI: 10.1155/2022/6499668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 01/16/2022] [Accepted: 01/27/2022] [Indexed: 12/22/2022] Open
Abstract
Idiopathic nephrotic syndrome (INS) is an important primary glomerular disease characterized by severe proteinuria. Evidence supports a role for T cell dysfunction in the pathogenesis of INS. Glucocorticoids are the primary therapy for INS; however, steroid-resistant NS (SRNS) patients are at a higher risk of drug-induced side effects and harbor poor prognosis. Although the exact mechanism of the resistance is unknown, the imbalances of T helper subtype 1 (Th1), Th2, and regulatory T cells (Tregs) and their cytokines may be involved in the pathogenesis of glucocorticoid responsiveness. Up to now, no confirmed biomarkers have been able to predict SRNS; however, a panel of cytokines may predict responsiveness and identify SRNS patients. Thus, the introduction of distinctive cytokines as novel biomarkers of SRNS enables both preventions of drug-related toxicity and earlier switch to more effective therapies. This review highlights the impacts of T cell population imbalances and their downstream cytokines on response to glucocorticoid responsiveness state in INS.
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Pronier E, Imanci A, Selimoglu-Buet D, Badaoui B, Itzykson R, Roger T, Jego C, Naimo A, Francillette M, Breckler M, Wagner-Ballon O, Figueroa ME, Aglave M, Gautheret D, Porteu F, Bernard OA, Vainchenker W, Delhommeau F, Solary E, Droin NM. Macrophage migration inhibitory factor is overproduced through EGR1 in TET2 low resting monocytes. Commun Biol 2022; 5:110. [PMID: 35115654 PMCID: PMC8814058 DOI: 10.1038/s42003-022-03057-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 01/06/2022] [Indexed: 12/14/2022] Open
Abstract
Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state, TET2 mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge, TET2 downregulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of TET2-decreased expression favors EGR1-driven transcription of MIF gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal TET2 downregulation in myeloid cells. To improve our understanding of the pathological role of TET2 mutations, Pronier, Imanci et al. use mice and human cells to show that TET2 downregulation promotes the production of macrophage migration inhibitory factor (MIF). In addition they show that whilst TET2 is recruited to the MIF promoter in healthy monocytes, decreased TET2 expression results in chronic overproduction of MIF - suggesting that MIF signaling could therefore constitute a potential therapeutic target for conditions associated with TET2 mutations.
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Affiliation(s)
- Elodie Pronier
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Owkin Lab, Owkin, Inc., New York, NY, 10003, USA
| | - Aygun Imanci
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France
| | - Dorothée Selimoglu-Buet
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France
| | - Bouchra Badaoui
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Département d'Hématologie et Immunologie Biologiques, 94000, Créteil, France
| | - Raphael Itzykson
- AP-HP, Service Hématologie Adultes, Hôpital Saint-Louis, 75010, Paris, France
| | - Thierry Roger
- Infectious Disease Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1011, Lausanne, Switzerland
| | - Chloé Jego
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France
| | - Audrey Naimo
- INSERM US23, CNRS UMS 3655, AMMICa, Genomic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Maëla Francillette
- INSERM US23, CNRS UMS 3655, AMMICa, Genomic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Marie Breckler
- INSERM US23, CNRS UMS 3655, AMMICa, Genomic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Orianne Wagner-Ballon
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Département d'Hématologie et Immunologie Biologiques, 94000, Créteil, France.,Université Paris Est Créteil, INSERM, IMRB, Equipe 9, 94010, Créteil, France
| | - Maria E Figueroa
- Human Genetics, University of Miami Miller School of Medicine, 33136, Miami, USA.,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 33136, Miami, USA
| | - Marine Aglave
- INSERM US23, CNRS UMS 3655, AMMICa, Bioinformatic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Daniel Gautheret
- INSERM US23, CNRS UMS 3655, AMMICa, Bioinformatic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Françoise Porteu
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France
| | - Olivier A Bernard
- Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France.,INSERM U1170, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - William Vainchenker
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France
| | - François Delhommeau
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, 75012, Paris, France.,AP-HP, Sorbonne Université, Hôpital Saint-Antoine, Service d'Hématologie et Immunologie Biologique, 75012, Paris, France
| | - Eric Solary
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France.,Hematology department, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Nathalie M Droin
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France. .,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France. .,INSERM US23, CNRS UMS 3655, AMMICa, Genomic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France.
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Sunil AA, Skaria T. Novel regulators of airway epithelial barrier function during inflammation: potential targets for drug repurposing. Expert Opin Ther Targets 2022; 26:119-132. [PMID: 35085478 DOI: 10.1080/14728222.2022.2035720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Endogenous inflammatory signaling molecules resulting from deregulated immune responses, can impair airway epithelial barrier function and predispose individuals with airway inflammatory diseases to exacerbations and lung infections. Targeting the specific endogenous factors disrupting the airway barrier therefore has the potential to prevent disease exacerbations without affecting the protective immune responses. AREAS COVERED Here, we review the endogenous factors and specific mechanisms disrupting airway epithelial barrier during inflammation and reflect on whether these factors can be specifically targeted by repurposed existing drugs. Literature search was conducted using PubMed, drug database of US FDA and European Medicines Agency until and including September 2021. EXPERT OPINION IL-4 and IL-13 signaling are the major pathways disrupting the airway epithelial barrier during airway inflammation. However, blocking IL-4/IL-13 signaling may adversely affect protective immune responses and increase susceptibility of host to infections. An alternate approach to modulate airway epithelial barrier function involves targeting specific downstream component of IL-4/IL-13 signaling or different inflammatory mediators responsible for regulation of airway epithelial barrier. Airway epithelium-targeted therapy using inhibitors of HDAC, HSP90, MIF, mTOR, IL-17A and VEGF may be a potential strategy to prevent airway epithelial barrier dysfunction in airway inflammatory diseases.
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Affiliation(s)
- Ahsan Anjoom Sunil
- School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India
| | - Tom Skaria
- School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India
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