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Ogger PP, Murray PJ. Dissecting inflammation in the immunemetabolomic era. Cell Mol Life Sci 2025; 82:182. [PMID: 40293552 PMCID: PMC12037969 DOI: 10.1007/s00018-025-05715-8] [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: 01/31/2025] [Revised: 04/11/2025] [Accepted: 04/12/2025] [Indexed: 04/30/2025]
Abstract
The role of immune metabolism, specific metabolites and cell-intrinsic and -extrinsic metabolic states across the time course of an inflammatory response are emerging knowledge. Targeted and untargeted metabolomic analysis is essential to understand how immune cells adapt their metabolic program throughout an immune response. In addition, metabolomic analysis can aid to identify pathophysiological patterns in inflammatory disease. Here, we discuss new metabolomic findings within the transition from inflammation to resolution, focusing on three key programs of immunity: Efferocytosis, IL-10 signaling and trained immunity. Particularly the tryptophan-derived metabolite kynurenine was identified as essential for efferocytosis and inflammation resolution as well as a potential biomarker in diverse inflammatory conditions. In summary, metabolomic analysis and integration with transcriptomic and proteomic data, high resolution imaging and spatial information is key to unravel metabolic drivers and dependencies during inflammation and progression to tissue-repair.
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Affiliation(s)
- Patricia P Ogger
- Immunoregulation Research Group, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany
| | - Peter J Murray
- Immunoregulation Research Group, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany.
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2
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Maes M, Vasupanrajit A, Jirakran K, Zhou B, Tunvirachaisakul C, Almulla AF. Simple dysmood disorder, a mild subtype of major depression, is not an inflammatory condition: Depletion of the compensatory immunoregulatory system. J Affect Disord 2025; 375:75-85. [PMID: 39848470 DOI: 10.1016/j.jad.2025.01.101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 09/13/2024] [Accepted: 01/18/2025] [Indexed: 01/25/2025]
Abstract
BACKGROUND A recent study conducted by the laboratory of the first author revealed that major depression is composed of two distinct subtypes: major dysmood disorder (MDMD) and simple dysmood disorder (SDMD). The latter is a less severe phenotype with fewer aberrant biological pathways. MDMD, but not SDMD, patients were identified to have highly sensitized cytokine/growth factor networks using stimulated whole blood cultures. However, no information regarding serum cytokines/chemokines/growth factors in SDMD is available. OBJECTIVES This case-control study compares 48 serum cytokines/chemokines/growth factors in academic students with SDMD (n = 64) and first episode (FE)-SDMD (n = 47) to those of control students (n = 44) using a multiplex assay. FINDINGS Both FE-SDMD and SDMD exhibited a notable inhibition of immune profiles, such as the compensatory immunoregulatory response system (CIRS) and alternative M2 macrophage and T helper-2 (Th-2) profiles. We observed a substantial reduction in the serum concentrations of five proteins: interleukin (IL)-4, IL-10, soluble IL-2 receptor (sIL-2R), IL-12p40, and macrophage colony-stimulating factor. A considerable proportion of the variability observed in suicidal behaviors (26.7 %) can be accounted for by serum IL-4, IL-10, and sIL-2R (all decreased), CCL11 (eotaxin) and granulocyte CSF (both increased). The same biomarkers (except for IL-10), accounted for 25.5 % of the variance in SDMS severity. A significant correlation exists between decreased levels of IL-4 and elevated ratings of the brooding type of rumination. CONCLUSIONS SDMD is characterized by the suppression of the CIRS profile, which signifies a disruption of immune homeostasis and tolerance, rather than the presence of an inflammatory response.
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Affiliation(s)
- Michael Maes
- Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, China; Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Ph.D. Program in Mental Health, Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Cognitive Impairment and Dementia Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Cognitive Fitness and Biopsychological Technology Research Unit, Faculty of Medicine Chulalongkorn University, Bangkok 10330, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria; Research Institute, Medical University of Plovdiv, Plovdiv, Bulgaria; Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
| | - Asara Vasupanrajit
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Ph.D. Program in Mental Health, Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Ketsupar Jirakran
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Ph.D. Program in Mental Health, Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Center of Excellence for Maximizing Children's Developmental Potential, Department of Pediatric, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Bo Zhou
- Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, China
| | - Chavit Tunvirachaisakul
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Ph.D. Program in Mental Health, Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Cognitive Impairment and Dementia Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Abbas F Almulla
- Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, China; Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq.
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Wang L, Xu L, Song S, Mo L, Liu L, Zhang H, Xiao X, Zhang A, Zhang H, Yang P. IL-10 signaling modulates PRKN methylation and influences STAT3 activity to drive regulatory macrophage differentiation. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167643. [PMID: 39734006 DOI: 10.1016/j.bbadis.2024.167643] [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: 09/26/2024] [Revised: 11/18/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
The pathogenesis of many immune disorders is linked to regulatory macrophage dysfunction. The mechanism underlying it is unclear. The objective of this study is to examine the mechanism by which the PRKN ubiquitin protein ligase (PRKN) inhibits the development of regulatory macrophages (Mreg). In this study, dust mite antigens were used as the specific allergens to establish an airway allergy (AA) mouse model. Flow cytometry cell sorting was used to isolate macrophages from the airway tissues. According to the results, the Prkn gene inhibition led to an increase in the number of Mregs in macrophages. Mregs demonstrated the capacity to suppress Th2 polarization, in which IL-10 played a critical role. Pan macrophages isolated from Prkn-deficient mice were more capable of suppressing the activities of other immune cells. PRKN was required for maintaining the hyperubiquitous status of signal transducer and transcriptional activator-3 (STAT3) in macrophages. Exposure to dust mite antigen increased the expression of PRKN in macrophages. IL-10 suppressed PRKN in macrophages by inducing its promoter hypermethylation. PRKN inhibition mitigated the experimental AA. To sum up, PRKN maintains the hyper ubiquitous status of STAT3 and restricts the expression of IL-10 in macrophages, which compromises their immune suppressive functions. Inhibition of PRKN increases Mreg development and mitigates AA. The data suggest that the regulation of Mreg has translation potential to be used in the treatment of immune disorders such as AA.
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Affiliation(s)
- Lihuan Wang
- Department of Allergy Medicine & Pulmonary and Critical Care Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Lingzhi Xu
- Department of Immunology, Basic Medical College of Weifang Medical University, Weifang, China
| | - Shuo Song
- Department of General Practice Medicine, Third Affiliated Hospital, Shenzhen University, Shenzhen, China
| | - Lihua Mo
- Department of General Practice Medicine, Third Affiliated Hospital, Shenzhen University, Shenzhen, China
| | - Le Liu
- State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University and Institute of Allergy & Immunology of Shenzhen University School of Medicine, Shenzhen, China
| | - Hanqing Zhang
- State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University and Institute of Allergy & Immunology of Shenzhen University School of Medicine, Shenzhen, China
| | - Xiaojun Xiao
- State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University and Institute of Allergy & Immunology of Shenzhen University School of Medicine, Shenzhen, China
| | - Aizhi Zhang
- Department of Critical Care Medicine, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Huanping Zhang
- Department of Allergy Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China.
| | - Pingchang Yang
- State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University and Institute of Allergy & Immunology of Shenzhen University School of Medicine, Shenzhen, China.
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Izzy S, Yahya T, Albastaki O, Abou-El-Hassan H, Aronchik M, Cao T, De Oliveira MG, Lu KJ, Moreira TG, da Silva P, Boucher ML, Beauchamp LC, S LeServe D, Brandao WN, Carolina Durão A, Lanser T, Montini F, Lee JH, Bernstock JD, Kaul M, Pasquarelli-do-Nascimento G, Chopra K, Krishnan R, Mannix R, Rezende RM, Quintana FJ, Butovsky O, Weiner HL. Nasal anti-CD3 monoclonal antibody ameliorates traumatic brain injury, enhances microglial phagocytosis and reduces neuroinflammation via IL-10-dependent T reg-microglia crosstalk. Nat Neurosci 2025; 28:499-516. [PMID: 40016353 PMCID: PMC11893472 DOI: 10.1038/s41593-025-01877-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/20/2024] [Indexed: 03/01/2025]
Abstract
Neuroinflammation plays a crucial role in traumatic brain injury (TBI), contributing to both damage and recovery, yet no effective therapy exists to mitigate central nervous system (CNS) injury and promote recovery after TBI. In the present study, we found that nasal administration of an anti-CD3 monoclonal antibody ameliorated CNS damage and behavioral deficits in a mouse model of contusional TBI. Nasal anti-CD3 induced a population of interleukin (IL)-10-producing regulatory T cells (Treg cells) that migrated to the brain and closely contacted microglia. Treg cells directly reduced chronic microglia inflammation and regulated their phagocytic function in an IL-10-dependent manner. Blocking the IL-10 receptor globally or specifically on microglia in vivo abrogated the beneficial effects of nasal anti-CD3. However, the adoptive transfer of IL-10-producing Treg cells to TBI-injured mice restored these beneficial effects by enhancing microglial phagocytic capacity and reducing microglia-induced neuroinflammation. These findings suggest that nasal anti-CD3 represents a promising new therapeutic approach for treating TBI and potentially other forms of acute brain injury.
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Affiliation(s)
- Saef Izzy
- Immunology of Brain Injury Program, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- Divisions of Stroke, Cerebrovascular, and Critical Care Neurology, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Taha Yahya
- Immunology of Brain Injury Program, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- Divisions of Stroke, Cerebrovascular, and Critical Care Neurology, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Omar Albastaki
- Immunology of Brain Injury Program, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- Divisions of Stroke, Cerebrovascular, and Critical Care Neurology, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hadi Abou-El-Hassan
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael Aronchik
- Immunology of Brain Injury Program, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Tian Cao
- Immunology of Brain Injury Program, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Marilia Garcia De Oliveira
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kuan-Jung Lu
- Immunology of Brain Injury Program, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Thais G Moreira
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Patrick da Silva
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Masen L Boucher
- Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Leah C Beauchamp
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Danielle S LeServe
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Wesley Nogueira Brandao
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ana Carolina Durão
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Toby Lanser
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Federico Montini
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Joon-Hyuk Lee
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Joshua D Bernstock
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Megha Kaul
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Kusha Chopra
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Rajesh Krishnan
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Rebekah Mannix
- Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Rafael M Rezende
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Francisco J Quintana
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Oleg Butovsky
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Howard L Weiner
- Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
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5
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Salehi M, Neshati Z, Ahanchian H, Tafrishi R, Pasdar A, Safi M, Karimiani EG. Hyper IgE Syndromes: Understanding, Management, and Future Perspectives: A Narrative Review. Health Sci Rep 2025; 8:e70497. [PMID: 40114756 PMCID: PMC11922810 DOI: 10.1002/hsr2.70497] [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: 09/21/2024] [Revised: 01/09/2025] [Accepted: 02/07/2025] [Indexed: 03/22/2025] Open
Abstract
Background and Aim Hyper IgE syndromes (HIES) are rare primary immunodeficiency characterized by susceptibility to specific infections, eczema, and elevated IgE levels. Pathogenic mutations in STAT3, IL6R, IL6ST, ERBB2IP, PGM3, ZNF431, SPINK5, TGFBR1/2, and CARD11 have been identified as genetic factors contributing to phenotypes of HIES lead to hindered differentiation and activity, aberrant signaling cascades and disrupting immune regulation. HIES present a diverse clinical symptoms, challenging diagnosis and management; understanding its pathophysiology, genetics, and immunological abnormalities offer hope for improved outcomes. In this review we aim to provide a comprehensive understanding of the condition and also discuss latest updates on pathological features, clinical spectrum and its variability, immunological abnormalities, inheritance patterns, new candidate genes, challenges, management strategies, epidemiology and future directions of HIES. Methods This review conducted an extensive search of information from multiple databases, including PubMed, Scopus, WHO, and ClinVar to ensure comprehensive coverage. Preference was given to articles published recently to capture the latest research and developments. Endnote was employed as a reference manager. The relevant literature was meticulously reviewed to address the objectives of the study. Results Missense, nonsense, and frameshift variants are commonly observed in HIES. Understanding these genetic mutations is key to diagnosing and managing conditions such as Hyper-IgE recurrent infection syndromes (linked to IL6R, STAT3, and ZNF341 mutations), Atopy associated with ERBIN mutations which links STAT3 and TGF-β pathway, Immunodeficiency 23 (caused by PGM3 mutations), Netherton syndrome (resulting from SPINK5 mutations), and Loeys-Dietz syndrome (related to TGFBR mutations). Each year, new genes and variants responsible for this type of immune deficiency are added to the list. Conclusion Although rare, HIES significantly impacts patients due to its complex medical manifestations and need for lifelong management. Identifying casual variants is essential for effective clinical management of these complex conditions.
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Affiliation(s)
- Mohammad Salehi
- Department of Biology, Faculty of Science Ferdowsi University of Mashhad Mashhad Iran
| | - Zeinab Neshati
- Department of Biology, Faculty of Science Ferdowsi University of Mashhad Mashhad Iran
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology Ferdowsi University of Mashhad Mashhad Iran
| | - Hamid Ahanchian
- Allergy Research Center Mashhad University of Medical Sciences Mashhad Iran
| | - Rana Tafrishi
- Allergy Research Center Mashhad University of Medical Sciences Mashhad Iran
| | - Alireza Pasdar
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
- Faculty of Medicine, Medical Genetics Research Centre Mashhad University of Medical Sciences Mashhad Iran
| | - Mojtaba Safi
- Department of Genetics Next Generation Genetic Polyclinic Mashhad Iran
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Shen Q, Hu W, Liu F, Dong S, Peng X, Zhong Y, Chen C, Zuo Y, Ge C, Li W, Zha W, Ye Z, Cao Z, Liao L. Dipropyl phthalate induces craniofacial chondrogenic defects in zebrafish embryos. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 290:117603. [PMID: 39721426 DOI: 10.1016/j.ecoenv.2024.117603] [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: 11/06/2024] [Revised: 12/20/2024] [Accepted: 12/20/2024] [Indexed: 12/28/2024]
Abstract
Dipropyl phthalate (DPRP), a plasticizer commonly utilized in the plastics industry, has been identified in food and the environment and has the potential to present a hazard to human health and the environment. In this study, the first comprehensive evaluation of DPRP-induced craniofacial chondrogenic defects was conducted using a zebrafish model. Zebrafish embryos were exposed to 1, 2, and 4 mg/L DPRP from 6 to 96 h post-fertilization. At 80 hpf, it was observed that exposure to DPRP resulted in craniofacial developmental malformations, which were mainly characterized by the shortening of the mandibular pharyngeal arches and the inability of the accompanying artery to elongate forward. The resulting phenotype was similar to that of micrognathia syndrome. Transcriptome sequencing and molecular docking analyses revealed that DPRP down-regulated chondrocyte-related genes and induced activation of the FoxO signaling pathway, which in turn interfered with cell proliferation and apoptosis. In this process, DPRP induced elevated levels of oxidative stress in the craniofacial pharyngeal arch while promoting inflammatory responses. This ultimately led to craniofacial chondrogenic malformations in zebrafish. The present study demonstrates that DPRP induces developmental toxicity of zebrafish craniofacial cartilage, which may have adverse effects on other aquatic organisms and humans.
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Affiliation(s)
- Qinyuan Shen
- The Affiliated Stomatological Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Oral Diseases, Jiangxi Provincial Clinical Research Center for Oral Diseases, Nanchang, Jiangxi 330006, PR China
| | - Weitao Hu
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Fasheng Liu
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Si Dong
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Xinya Peng
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Yihang Zhong
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Chao Chen
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Yuhua Zuo
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Chenkai Ge
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Weirong Li
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Wenwen Zha
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Zhijun Ye
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China
| | - Zigang Cao
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China.
| | - Lan Liao
- The Affiliated Stomatological Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Oral Diseases, Jiangxi Provincial Clinical Research Center for Oral Diseases, Nanchang, Jiangxi 330006, PR China; Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs and Epigenetics, Clinical Research Center of Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, Jiangxi 343009, PR China; The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, PR China.
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7
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Zaroon, Aslam S, Hafsa, Mustafa U, Fatima S, Bashir H. Interleukin in Immune-Mediated Diseases: An Updated Review. Mol Biotechnol 2024:10.1007/s12033-024-01347-8. [PMID: 39715931 DOI: 10.1007/s12033-024-01347-8] [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: 08/20/2024] [Accepted: 11/29/2024] [Indexed: 12/25/2024]
Abstract
The immune system comprises various regulators and effectors that elicit immune responses against various attacks on the body. The pathogenesis of autoimmune diseases is derived from the deregulated expression of cytokines, the major regulators of the immune system. Among cytokines, interleukins have a major influence on immune-mediated diseases. These interleukins initiate the immune response against healthy and normal cells of the body, resulting in immune-mediated disease. The major interleukins in this respect are IL-1, IL-3, IL-4, IL-6, IL-10 and IL-12 which cause immune responses such as excessive inflammation, loss of immune tolerance, altered T-cell differentiation, immune suppression dysfunction, and inflammatory cell recruitment. Systemic Lupus Erythematosus (SLE) is an autoimmune illness characterized by dysregulation of interleukins. These immune responses are the signs of diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, type I diabetes, and multiple sclerosis.
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Affiliation(s)
- Zaroon
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Shakira Aslam
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Hafsa
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Usama Mustafa
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Sana Fatima
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Hamid Bashir
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan.
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8
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Liao JX, Huang QM, Pan ZC, Wu J, Zhang WJ. The anti-inflammatory and immunomodulatory effects of olfactory ensheathing cells transplantation in spinal cord injury and concomitant pathological pain. Eur J Pharmacol 2024; 982:176950. [PMID: 39214270 DOI: 10.1016/j.ejphar.2024.176950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 07/26/2024] [Accepted: 08/27/2024] [Indexed: 09/04/2024]
Abstract
Spinal cord injury (SCI) is a serious and disabling injury that is often accompanied by neuropathic pain (NeP), which severely affects patients' motor and sensory functions and reduces their quality of life. Currently, there is no specific treatment for treating SCI and relieving the accompanying pain, and we can only rely on medication and physical rehabilitation, both of which are ineffective. Researchers have recently identified a novel class of glial cells, olfactory ensheathing cells (OECs), which originate from the olfactory system. Transplantation of OECs into damaged spinal cords has demonstrated their capacity to repair damaged nerves, improve the microenvironment at the point of injury, and They can also restore neural connectivity and alleviate the patient's NeP to a certain extent. Although the effectiveness of OECs transplantation has been confirmed in experiments, the specific mechanisms by which it repairs the spinal cord and relieves pain have not been articulated. Through a review of the literature, it has been established that the ability of OECs to repair and relieve pain is inextricably linked to its anti-inflammatory and immunomodulatory effects. In this regard, it is imperative to gain a deeper understanding of how OECs exert their anti-inflammatory and immunomodulatory effects. The objective of this paper is to provide a comprehensive overview of the mechanisms by which OECs exert anti-inflammatory and immunomodulatory effects. We aim to manipulate the immune microenvironment at the transplantation site through the intervention of cytokines and immune cells, with the goal of enhancing OECs' function or creating a conducive microenvironment for OECs' survival. This approach is expected to improve the therapeutic efficacy of OECs in clinical settings. However, numerous fundamental and clinical challenges remain to be addressed if OEC transplantation therapy is to become a standardized treatment in clinical practice.
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Affiliation(s)
- Jun-Xiang Liao
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi province, China
| | - Qi-Ming Huang
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi province, China
| | - Zhi-Cheng Pan
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi province, China
| | - Jie Wu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi province, China
| | - Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi province, China.
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9
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Niu K, Zhang C, Liu C, Wu W, Yan Y, Zheng A, Liu S, Shi Z, Yang M, Wang W, Xiao Q. An unexpected role of IL10 in mesoderm induction and differentiation from pluripotent stem cells: Implications in zebrafish angiogenic sprouting, vascular organoid development, and therapeutic angiogenesis. Eur J Cell Biol 2024; 103:151465. [PMID: 39471724 DOI: 10.1016/j.ejcb.2024.151465] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/21/2024] [Accepted: 10/21/2024] [Indexed: 11/01/2024] Open
Abstract
Mesoderm induction is a crucial step for vascular cell specification, vascular development and vasculogenesis. However, the cellular and molecular mechanisms underlying mesoderm induction remain elusive. In the present study, a chemically-defined differentiation protocol was used to induce mesoderm formation and generate functional vascular cells including smooth muscle cells (SMCs) and endothelial cells (ECs) from human induced pluripotent stem cells (hiPSCs). Zebrafish larvae were used to detect an in vivo function of interleukin 10 (IL10) in mesoderm formation and vascular development. A three dimensional approach was used to create hiPSC-derived blood vessel organoid (BVO) and explore a potential impact of IL10 on BVO formation. A murine model hind limb ischemia was applied to investigate a therapeutic potential of hiPSC-derived cells treated with or without IL10 during differentiation. We found that IL10 was significantly and specifically up-regulated during mesoderm stage of vascular differentiation. IL10 addition in mesoderm induction media dramatically increased mesoderm induction and vascular cell generation from hiPSCs, whereas an opposite effect was observed with IL10 inhibition. Mechanistic studies revealed that IL10 promotes mesoderm formation and vascular cell differentiation by activating signal transducer and activator of transcription 3 signal pathway. Functional studies with an in vivo model system confirmed that knockdown of IL10 using morpholino antisense oligonucleotides in zebrafish larvae caused defective mesoderm formation, angiogenic sprouting and vascular development. Additionally, our data also show IL10 promotes blood vessel organoid development and enhances vasculogenesis and angiogenesis. Importantly, we demonstrate that IL10 treatment during mesoderm induction stage enhances blood flow perfusion recovery and increases vasculogenesis and therapeutic angiogenesis after hind limb ischemia. Our data, therefore, demonstrate a regulatory role for IL10 in mesoderm formation from hiPSCs and during zebrafish vascular development, providing novel insights into mesoderm induction and vascular cell specifications.
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Affiliation(s)
- Kaiyuan Niu
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London EC1M 6BQ, UK; Department of Otolaryngology, Head & Neck Surgery, First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei, Anhui 230022, PR China
| | - Chengxin Zhang
- Cardiovascular Surgery, First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei, Anhui 230022, PR China
| | - Chenxin Liu
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Wei Wu
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, PR China
| | - Yi Yan
- Department of Cardiology, Translational Research Center for Regenerative Medicine and 3D Printing Technologies, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, PR China
| | - Ancheng Zheng
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Silin Liu
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Zhenning Shi
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Mei Yang
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Wen Wang
- Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London EC1M 6BQ, UK.
| | - Qingzhong Xiao
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
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10
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Xue X, Zhou H, Gao J, Li X, Wang J, Bai W, Bai Y, Fan L, Chang H, Shi S. The impact of traditional Chinese medicine and dietary compounds on modulating gut microbiota in hepatic fibrosis: A review. Heliyon 2024; 10:e38339. [PMID: 39391468 PMCID: PMC11466535 DOI: 10.1016/j.heliyon.2024.e38339] [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: 09/02/2024] [Revised: 09/21/2024] [Accepted: 09/23/2024] [Indexed: 10/12/2024] Open
Abstract
Traditional Chinese medicine (TCM) and dietary compounds have a profound influence on the regulation of gut microbiota (GM) in hepatic fibrosis (HF). Certain substances found in both food and herbs that are edible and medicinal, such as dietary fiber, polyphenols, and polysaccharides, can generate beneficial metabolites like short-chain fatty acids (SCFAs), bile acids (BAs), and tryptophan (Trp). These compounds contribute to regulate the GM, reduce levels of endotoxins in the liver, and alleviate fibrosis and inflammation in the liver. Furthermore, they enhance the composition and functionality of GM, promoting the growth of beneficial bacteria while inhibiting the proliferation of harmful bacteria. These mechanisms mitigate the inflammatory response in the intestines and maintain the integrity of the intestinal barrier. The purpose of this review is to analyze how the GM regulates the pathogenesis of HF, evaluate the regulatory effect of TCM and dietary compounds on the intestinal microflora, with a particular emphasis on modulating flora structure, enhancing gut barrier function, and addressing associated pathogenic factors, thereby provide new insights for the treatment of HF.
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Affiliation(s)
- Xingting Xue
- Department of Pharmacy, Baotou Medical College, Baotou, 014040, China
| | - Hongbing Zhou
- Department of Pharmacy, Baotou Medical College, Baotou, 014040, China
| | - Jiaxing Gao
- Department of Pharmacy, Baotou Medical College, Baotou, 014040, China
| | - Xinghua Li
- Changzhi People's Hospital, The Affiliated Hospital of Changzhi Medical College, Changzhi, Shanxi Province, China
| | - Jia Wang
- Department of Pharmacy, Baotou Medical College, Baotou, 014040, China
| | - Wanfu Bai
- Department of Pharmacy, Baotou Medical College, Baotou, 014040, China
| | - Yingchun Bai
- Department of Pharmacy, Baotou Medical College, Baotou, 014040, China
| | - Liya Fan
- Department of Pharmacy, Baotou Medical College, Baotou, 014040, China
| | - Hong Chang
- Department of Pharmacy, Baotou Medical College, Baotou, 014040, China
| | - Songli Shi
- Department of Pharmacy, Baotou Medical College, Baotou, 014040, China
- Institute of Bioactive Substance and Function of Mongolian Medicine and Chinese Materia Medica, Baotou Medical College, Baotou, China
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11
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Kang K, Lin X, Chen P, Liu H, Liu F, Xiong W, Li G, Yi M, Li X, Wang H, Xiang B. T cell exhaustion in human cancers. Biochim Biophys Acta Rev Cancer 2024; 1879:189162. [PMID: 39089484 DOI: 10.1016/j.bbcan.2024.189162] [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: 01/30/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024]
Abstract
T cell exhaustion refers to a progressive state in which T cells become functionally impaired due to sustained antigenic stimulation, which is characterized by increased expression of immune inhibitory receptors, but weakened effector functions, reduced self-renewal capacity, altered epigenetics, transcriptional programme and metabolism. T cell exhaustion is one of the major causes leading to immune escape of cancer, creating an environment that supports tumor development and metastatic spread. In addition, T cell exhaustion plays a pivotal role to the efficacy of current immunotherapies for cancer. This review aims to provide a comprehensive view of roles of T cell exhaustion in cancer development and progression. We summerized the regulatory mechanisms that involved in T cell exhaustion, including transcription factors, epigenetic and metabolic reprogramming events, and various microenvironmental factors such as cytokines, microorganisms, and tumor autocrine substances. The paper also discussed the challenges posed by T cell exhaustion to cancer immunotherapies, including immune checkpoint blockade (ICB) therapies and chimeric antigen receptor T cell (CAR-T) therapy, highlightsing the obstacles encountered in ICB therapies and CAR-T therapies due to T cell exhaustion. Finally, the article provides an overview of current therapeutic options aimed to reversing or alleviating T cell exhaustion in ICB and CAR-T therapies. These therapeutic approaches seek to overcome T cell exhaustion and enhance the effectiveness of immunotherapies in treating tumors.
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Affiliation(s)
- Kuan Kang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Xin Lin
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Pan Chen
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China
| | - Huai Liu
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Feng Liu
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Wei Xiong
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Guiyuan Li
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Mei Yi
- Department of Dermatology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xiayu Li
- Hunan Key Laboratory of Nonresolving Infammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
| | - Hui Wang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.
| | - Bo Xiang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China; FuRong Laboratory, Changsha 410078, Hunan, China.
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12
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Rengifo T, Bishir M, Huang W, Snyder M, Chang SL. Network meta-analysis of the molecular mechanisms and signaling pathways underlying alcohol-induced thymic atrophy. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:795-809. [PMID: 38553251 PMCID: PMC11161038 DOI: 10.1111/acer.15292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/28/2024] [Accepted: 02/22/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND Thymic atrophy is characterized by loss of thymocytes, destruction of thymic architecture, and a subsequent decrease in naïve T cells with compromised immunity. Thymic atrophy occurs during aging. Environmental factors including alcohol misuse also induce thymic atrophy. Despite the link between alcohol misuse and thymic atrophy, the underlying mechanism is understudied. We aimed to identify molecules and signaling pathways that underly alcohol-induced thymic atrophy during aging. METHODS F344 rats were given 3-day binge-ethanol (4.8 g/kg/day; 52% w/v; i.g.) and the thymus was collected and weighed. Molecular mechanisms underlying ethanol-induced thymic atrophy were investigated by network meta-analysis using the QIAGEN Ingenuity Pathway Analysis (IPA). The molecules associated with ethanol were identified from the QIAGEN Knowledge Base (QKB) and those associated with thymic atrophy were identified from QKB and Mouse Genome Informatics (MGI). Aging-mediated Differential Expression Genes (DEGs) from mouse thymocytes were obtained from the Gene Expression Omnibus (GEO) database (GSE132136). The relationship between the molecules and associated signaling pathways were studied using IPA. RESULTS Binge-ethanol decreased thymic weight in F344 rats. Our meta-analysis using IPA identified molecules commonly shared by ethanol and thymic atrophy through which simulation with ethanol increased thymic atrophy. We then obtained aging-mediated DEGs from the atrophied thymocytes. We found that ethanol contributed to thymic atrophy through modulation of the aging-mediated DEGs. Our network meta-analysis suggests that ethanol may augment thymic atrophy through increased expression of cytokines (e.g., IL-6, IL-17A and IL-33) along with their regulators (e.g., STAT1 and STAT3). CONCLUSIONS Exposure to alcohol may augment thymic atrophy by altering the activity of key inflammatory mediators, such as STAT family members and inflammatory cytokines. These findings provide insights into the signaling pathways and upstream regulators that underly alcohol-induced thymic atrophy during aging, suggesting that alcohol consumption could prepone thymic atrophy.
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Affiliation(s)
- Tatiana Rengifo
- Institute of NeuroImmune Pharmacology, Seton Hall University
- Department of Biological Sciences, Seton Hall University
| | - Muhammed Bishir
- Institute of NeuroImmune Pharmacology, Seton Hall University
- Department of Biological Sciences, Seton Hall University
| | - Wenfei Huang
- Institute of NeuroImmune Pharmacology, Seton Hall University
- Department of Biological Sciences, Seton Hall University
| | | | - Sulie L. Chang
- Institute of NeuroImmune Pharmacology, Seton Hall University
- Department of Biological Sciences, Seton Hall University
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13
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Liu J, Zhang B, Zhang G, Shang D. Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point? Front Immunol 2024; 15:1345838. [PMID: 38449875 PMCID: PMC10915070 DOI: 10.3389/fimmu.2024.1345838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 01/29/2024] [Indexed: 03/08/2024] Open
Abstract
Overcoming the immunosuppressive tumor microenvironment and identifying widely used immunosuppressants with minimal side effects are two major challenges currently hampering cancer immunotherapy. Regulatory T cells (Tregs) are present in almost all cancer tissues and play an important role in preserving autoimmune tolerance and tissue homeostasis. The tumor inflammatory microenvironment causes the reprogramming of Tregs, resulting in the conversion of Tregs to immunosuppressive phenotypes. This process ultimately facilitates tumor immune escape or tumor progression. However, current systemic Treg depletion therapies may lead to severe autoimmune toxicity. Therefore, it is crucial to understand the mechanism of Treg reprogramming and develop immunotherapies that selectively target Tregs within tumors. This article provides a comprehensive review of the potential mechanisms involved in Treg cell reprogramming and explores the application of Treg cell immunotherapy. The interference with reprogramming pathways has shown promise in reducing the number of tumor-associated Tregs or impairing their function during immunotherapy, thereby improving anti-tumor immune responses. Furthermore, a deeper understanding of the mechanisms that drive Treg cell reprogramming could reveal new molecular targets for future treatments.
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Affiliation(s)
- Jinming Liu
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Biao Zhang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Guolin Zhang
- Department of Cardiology, The Second Hospital of Dalian Medical University, Dalian, China
| | - Dong Shang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
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14
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Mathieu C, Wiedeman A, Cerosaletti K, Long SA, Serti E, Cooney L, Vermeiren J, Caluwaerts S, Van Huynegem K, Steidler L, Blomme S, Rottiers P, Nepom GT, Herold KC. A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab. Diabetologia 2024; 67:27-41. [PMID: 37782353 PMCID: PMC10709251 DOI: 10.1007/s00125-023-06014-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/21/2023] [Indexed: 10/03/2023]
Abstract
AIMS/HYPOTHESIS We hypothesised that islet beta cell antigen presentation in the gut along with a tolerising cytokine would lead to antigen-specific tolerance in type 1 diabetes. We evaluated this in a parallel open-label Phase 1b study using oral AG019, food-grade Lactococcus lactis bacteria genetically modified to express human proinsulin and human IL-10, as a monotherapy and in a parallel, randomised, double-blind Phase 2a study using AG019 in combination with teplizumab. METHODS Adults (18-42 years) and adolescents (12-17 years) with type 1 diabetes diagnosed within 150 days were enrolled, with documented evidence of at least one autoantibody and a stimulated peak C-peptide level >0.2 nmol/l. Participants were allocated to interventions using interactive response technology. We treated 42 people aged 12-42 years with recent-onset type 1 diabetes, 24 with Phase 1b monotherapy (open-label) and 18 with Phase 2a combination therapy. In the Phase 2a study, after treatment of the first two open-label participants, all people involved were blinded to group assignment, except for the Data Safety Monitoring Board members and the unblinded statistician. The primary endpoint was safety and tolerability based on the incidence of treatment-emergent adverse events, collected up to 6 months post treatment initiation. The secondary endpoints were pharmacokinetics, based on AG019 detection in blood and faeces, and pharmacodynamic activity. Metabolic and immune endpoints included stimulated C-peptide levels during a mixed meal tolerance test, HbA1c levels, insulin use, and antigen-specific CD4+ and CD8+ T cell responses using an activation-induced marker assay and pooled tetramers, respectively. RESULTS Data from 24 Phase 1b participants and 18 Phase 2a participants were analysed. No serious adverse events were reported and none of the participants discontinued AG019 due to treatment-emergent adverse events. No systemic exposure to AG019 bacteria, proinsulin or human IL-10 was demonstrated. In AG019 monotherapy-treated adults, metabolic variables were stabilised up to 6 months (C-peptide, insulin use) or 12 months (HbA1c) post treatment initiation. In participants treated with AG019/teplizumab combination therapy, all measured metabolic variables stabilised or improved up to 12 months and CD8+ T cells with a partially exhausted phenotype were significantly increased at 6 months. Circulating preproinsulin-specific CD4+ and CD8+ T cells were detected before and after treatment, with a reduction in the frequency of preproinsulin-specific CD8+ T cells after treatment with monotherapy or combination therapy. CONCLUSIONS/INTERPRETATION Oral delivery of AG019 was well tolerated and safe as monotherapy and in combination with teplizumab. AG019 was not shown to interfere with the safety profile of teplizumab and may have additional biological effects, including changes in preproinsulin-specific T cells. These preliminary data support continuing studies with this agent alone and in combination with teplizumab or other systemic immunotherapies in type 1 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT03751007, EudraCT 2017-002871-24 FUNDING: This study was funded by Precigen ActoBio.
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Affiliation(s)
- Chantal Mathieu
- Clinical and Experimental Endocrinology, University Hospital of Leuven, Leuven, Belgium
| | - Alice Wiedeman
- Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Karen Cerosaletti
- Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - S Alice Long
- Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | | | | | | | | | | | | | | | | | | | - Kevan C Herold
- Department of Immunology and Internal Medicine, Yale University, New Haven, CT, USA.
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15
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Ouyang P, Tao Y, Wei W, Li Q, Liu S, Ren Y, Huang X, Chen D, Geng Y. Spring Viremia of Carp Virus Infection Induces Carp IL-10 Expression, Both In Vitro and In Vivo. Microorganisms 2023; 11:2812. [PMID: 38004823 PMCID: PMC10673272 DOI: 10.3390/microorganisms11112812] [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: 09/19/2023] [Revised: 10/28/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Interleukin-10 (IL-10) is a pleiotropic cytokine with both immune enhancement and immunosuppression activities, but the main role is immunosuppression and anti-inflammatory ability. In order to use the immunosuppressive function of IL-10, many viruses, such as SARS-CoV-2, hepatitis B virus and EB virus, can evade the host's immune surveillance and clearance by increasing the expression of host IL-10. However, it has not been reported whether the aquatic animal infection virus can upregulate the expression of host IL-10 and the mechanisms are still unknown. Spring viremia of carp (SVC) is a fatal viral disease for many fish species and is caused by spring viremia of carp virus (SVCV). This disease has caused significant economic losses in the aquaculture industry worldwide. In this study, the expression of carp IL-10 with or without infection of SVCV in epithelioma papulosum cyprinid (EPC) cells, carp head kidney (cHK) primary cells and common carp tissues were analyzed using RT-PCR and ELISA. The results show that SVCV infection induced carp IL-10 mRNA and protein expression, both in vitro and in vivo. However, the upregulation of carp IL-10 by SVCV was hindered by specific inhibitors of the JAK inhibitor (CP-690550), STAT3 inhibitor (STA-21), NF-κB inhibitor (BAY11-7082) and p38 MAPK (mitogen-activated protein kinase) inhibitor (SB202190), but not JNK inhibitor (SP600125). Furthermore, the results demonstrated that JAK1, JAK2, JAK3, TYK2 and STAT5 played important roles in carp IL-10 production induced by SVCV infection. Taken together, SVCV infection significantly induced carp IL-10 expression and the upregulation trigged in JAK-STAT, NF-κB and p38MAPK pathways. To our knowledge, this is the first time that a fish infection virus upregulated the host IL-10 expression through the JAK-STAT, NF-κB and p38MAPK pathways. Altogether, fish viruses may have a similar mechanism as human or other mammalian viruses to escape host immune surveillance and clearance.
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Affiliation(s)
- Ping Ouyang
- Department of Basic Veterinary, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Q.L.); (S.L.); (Y.R.); (Y.G.)
| | - Yu Tao
- Department of Basic Veterinary, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Q.L.); (S.L.); (Y.R.); (Y.G.)
| | - Wenyan Wei
- Chengdu Academy of Agriculture and Forestry Sciences, Chengdu 611130, China;
| | - Qiunan Li
- Department of Basic Veterinary, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Q.L.); (S.L.); (Y.R.); (Y.G.)
| | - Shuya Liu
- Department of Basic Veterinary, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Q.L.); (S.L.); (Y.R.); (Y.G.)
| | - Yongqiang Ren
- Department of Basic Veterinary, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Q.L.); (S.L.); (Y.R.); (Y.G.)
| | - Xiaoli Huang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (X.H.); (D.C.)
| | - Defang Chen
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (X.H.); (D.C.)
| | - Yi Geng
- Department of Basic Veterinary, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.T.); (Q.L.); (S.L.); (Y.R.); (Y.G.)
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Liang Y, Shen L, Ni W, Ding Y, Yang W, Gu T, Zhang C, Yik JHN, Haudenschild DR, Fan S, Shen S, Hu Z. CircGNB1 drives osteoarthritis pathogenesis by inducing oxidative stress in chondrocytes. Clin Transl Med 2023; 13:e1358. [PMID: 37537733 PMCID: PMC10400757 DOI: 10.1002/ctm2.1358] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) have risen to prominence as important regulators of biological processes. This study investigated whether circGNB1 functions as a competitive endogenous RNA to regulate the pathological process of oxidative stress in age-related osteoarthritis (OA). METHODS The relationship between circGNB1 expression and oxidative stress/OA severity was determined in cartilages from OA patients at different ages. The biological roles of circGNB1 in oxidative stress and OA progression, and its downstream targets were determined using gain- and loss-of-function experiments in various biochemical assays in human chondrocytes (HCs). The in vivo effects of circGNB1 overexpression and knockdown were also determined using a destabilization of the medial meniscus (DMM) mouse model. RESULTS Increased circGNB1 expression was detected in HCs under oxidative and inflammatory stress and in the cartilage of older individuals. Mechanistically, circGNB1 sponged miR-152-3p and thus blocked its interaction with its downstream mRNA target, ring finger protein 219 (RNF219), which in turn stabilized caveolin-1 (CAV1) by preventing its ubiquitination at the K47 residue. CircGNB1 inhibited IL-10 signalling by antagonizing miR-152-3p-mediated RNF219 and CAV1 inhibition. Consequently, circGNB1 overexpression promoted OA progression by enhancing catabolic factor expression and oxidative stress and by suppressing anabolic genes in vitro and in vivo. Furthermore, circGNB1 knockdown alleviated the severity of OA, whereas circGNB1 overexpression had the opposite effect in a DMM mouse model of OA. CONCLUSION CircGNB1 regulated oxidative stress and OA progression via the miR-152-3p/RNF219/CAV1 axis. Modulating circGNB1 could be an effective strategy for treating OA.
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Affiliation(s)
- Yi Liang
- Department of Orthopedic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang ProvinceHangzhouChina
| | - Lifeng Shen
- Department of Orthopedic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang ProvinceHangzhouChina
| | - Weiyu Ni
- Department of Orthopedic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang ProvinceHangzhouChina
| | - Yuhong Ding
- Department of Orthopedic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang ProvinceHangzhouChina
| | - Wentao Yang
- Department of Orthopedic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang ProvinceHangzhouChina
| | - Tianyuan Gu
- Department of Orthopedic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang ProvinceHangzhouChina
| | - Chenfeng Zhang
- Department of Orthopedic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang ProvinceHangzhouChina
| | - Jasper H. N. Yik
- Ellison Musculoskeletal Research CenterDepartment of Orthopaedic SurgeryUniversity of California SystemDavisCaliforniaUSA
| | - Dominik R. Haudenschild
- Ellison Musculoskeletal Research CenterDepartment of Orthopaedic SurgeryUniversity of California SystemDavisCaliforniaUSA
| | - Shunwu Fan
- Department of Orthopedic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang ProvinceHangzhouChina
| | - Shuying Shen
- Department of Orthopedic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang ProvinceHangzhouChina
| | - Ziang Hu
- Department of Orthopedic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang ProvinceHangzhouChina
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Hieber C, Grabbe S, Bros M. Counteracting Immunosenescence-Which Therapeutic Strategies Are Promising? Biomolecules 2023; 13:1085. [PMID: 37509121 PMCID: PMC10377144 DOI: 10.3390/biom13071085] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/03/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Aging attenuates the overall responsiveness of the immune system to eradicate pathogens. The increased production of pro-inflammatory cytokines by innate immune cells under basal conditions, termed inflammaging, contributes to impaired innate immune responsiveness towards pathogen-mediated stimulation and limits antigen-presenting activity. Adaptive immune responses are attenuated as well due to lowered numbers of naïve lymphocytes and their impaired responsiveness towards antigen-specific stimulation. Additionally, the numbers of immunoregulatory cell types, comprising regulatory T cells and myeloid-derived suppressor cells, that inhibit the activity of innate and adaptive immune cells are elevated. This review aims to summarize our knowledge on the cellular and molecular causes of immunosenescence while also taking into account senescence effects that constitute immune evasion mechanisms in the case of chronic viral infections and cancer. For tumor therapy numerous nanoformulated drugs have been developed to overcome poor solubility of compounds and to enable cell-directed delivery in order to restore immune functions, e.g., by addressing dysregulated signaling pathways. Further, nanovaccines which efficiently address antigen-presenting cells to mount sustained anti-tumor immune responses have been clinically evaluated. Further, senolytics that selectively deplete senescent cells are being tested in a number of clinical trials. Here we discuss the potential use of such drugs to improve anti-aging therapy.
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Affiliation(s)
- Christoph Hieber
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
- Institute of Molecular Biology (IMB), Ackermannweg 4, 55128 Mainz, Germany
| | - Stephan Grabbe
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
- Institute of Molecular Biology (IMB), Ackermannweg 4, 55128 Mainz, Germany
| | - Matthias Bros
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
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18
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Mo L, Liu Y, Xu X, Wang X, Zhang S, Hu S, Wu Y, Tang Z, Huang Q, Li J, Sun X, Yang P. Endoplasmic reticulum stress impairs the immune regulation property of macrophages in asthmatic patients. Clin Immunol 2023; 252:109639. [PMID: 37172666 DOI: 10.1016/j.clim.2023.109639] [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: 03/16/2023] [Revised: 05/01/2023] [Accepted: 05/09/2023] [Indexed: 05/15/2023]
Abstract
The current study aims to characterize the counteraction of M2 cells in response to Endoplasmic reticulum (ER) stress. ER stress was detected in bronchoalveolar lavage fluids (BALF) Mϕs, which was at unresolved state in asthma patients. A positive correlation was detected between ER stress in Mϕs and lung functions/allergic mediators/Th2 cytokines in BALF or specific IgE in the serum. Levels of immune regulatory mediator in the BALF were negatively correlated to ER stress in BALF Mϕs. The ER stress state influenced the immune regulatory property of BALF Mϕ. Exposure to environmental pollutant, 3-metheyl-4-nitrophenol, exacerbated ER stress in Mϕ, which affected the Mϕ phenotyping. Exacerbation of ER stress suppressed the expression of IL-10 and programmed cell death protein-1 (PD-1) in Mϕs by increasing the expression of the ring finger protein 20 (Rnf20). Conditional inhibition of Rnf20 in Mϕs attenuated experimental airway allergy.
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Affiliation(s)
- Lihua Mo
- Department of General Practice Medicine and Respirology, Third Affiliated Hospital of Shenzhen University, Shenzhen, China; Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China; Institute of Allergy & Immunology of Shenzhen University, State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University, Shenzhen, China
| | - Yu Liu
- Department of General Practice Medicine and Respirology, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Xuejie Xu
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China; Institute of Allergy & Immunology of Shenzhen University, State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University, Shenzhen, China
| | - Xinxin Wang
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China; Institute of Allergy & Immunology of Shenzhen University, State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University, Shenzhen, China
| | - Shuang Zhang
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China; Institute of Allergy & Immunology of Shenzhen University, State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University, Shenzhen, China
| | - Suqin Hu
- Department of General Practice Medicine and Respirology, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Yongjin Wu
- Department of Allergy, Longgang ENT Hospital, Shenzhen, China
| | - Zhiyuan Tang
- Department of Allergy, Longgang ENT Hospital, Shenzhen, China
| | - Qinmiao Huang
- Department of General Practice Medicine and Respirology, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Jing Li
- Department of Allergy, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Xizhuo Sun
- Department of General Practice Medicine and Respirology, Third Affiliated Hospital of Shenzhen University, Shenzhen, China.
| | - Pingchang Yang
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China; Institute of Allergy & Immunology of Shenzhen University, State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University, Shenzhen, China.
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19
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Affiliation(s)
- Ellen M Gravallese
- From the Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston (E.M.G.); and Frazer Institute, University of Queensland, Brisbane, Australia (R.T.)
| | - Ranjeny Thomas
- From the Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston (E.M.G.); and Frazer Institute, University of Queensland, Brisbane, Australia (R.T.)
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20
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Guo Z, Chen F, Zhao S, Zhang Z, Zhang H, Bai L, Zhang Z, Li Y. IL-10 Promotes CXCL13 Expression in Macrophages Following Foot-and-Mouth Disease Virus Infection. Int J Mol Sci 2023; 24:ijms24076322. [PMID: 37047294 PMCID: PMC10093876 DOI: 10.3390/ijms24076322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/13/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Foot-and-mouth disease (FMD) is one of the most contagious livestock diseases in the world, posing a constant global threat to the animal trade and national economies. The chemokine C-X-C motif chemokine ligand 13 (CXCL13), a biomarker for predicting disease progression in some diseases, was recently found to be increased in sera from mice infected with FMD virus (FMDV) and to be associated with the progression and severity of the disease. However, it has not yet been determined which cells are involved in producing CXCL13 and the signaling pathways controlling CXCL13 expression in these cells. In this study, the expression of CXCL13 was found in macrophages and T cells from mice infected with FMDV, and CXCL13 was produced in bone-marrow-derived macrophages (BMDMs) by activating the nuclear factor-kappaB (NF-κB) and JAK/STAT pathways following FMDV infection. Interestingly, CXCL13 concentration was decreased in sera from interleukin-10 knock out (IL-10-/-) mice or mice blocked IL-10/IL-10R signaling in vivo after FMDV infection. Furthermore, CXCL13 was also decreased in IL-10-/- BMDMs and BMDMs treated with anti-IL-10R antibody following FMDV infection in vitro. Lastly, it was demonstrated that IL-10 regulated CXCL13 expression via JAK/STAT rather than the NF-κB pathway. In conclusion, the study demonstrated for the first time that macrophages and T cells were the cellular sources of CXCL13 in mice infected with FMDV; CXCL13 was produced in BMDMs via NF-κB and JAK/STAT pathways; and IL-10 promoted CXCL13 expression in BMDMs via the JAK/STAT pathway.
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Affiliation(s)
- Zijing Guo
- College of Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu 610041, China
| | - Fei Chen
- State Key Laboratory on Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730030, China
| | - Shuaiyang Zhao
- State Key Laboratory on Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730030, China
| | - Zhixiong Zhang
- State Key Laboratory on Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730030, China
| | - Huijun Zhang
- State Key Laboratory on Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730030, China
| | - Ling Bai
- State Key Laboratory on Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730030, China
| | - Zhidong Zhang
- College of Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu 610041, China
- Correspondence: (Z.Z.); (Y.L.); Tel.: +86-028-85528276 (Z.Z. & Y.L.)
| | - Yanmin Li
- College of Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu 610041, China
- Correspondence: (Z.Z.); (Y.L.); Tel.: +86-028-85528276 (Z.Z. & Y.L.)
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21
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Braun Lipoprotein Protects against Escherichia coli-Induced Inflammatory Responses and Lethality in Mice. Microbiol Spectr 2023:e0354122. [PMID: 36916913 PMCID: PMC10100777 DOI: 10.1128/spectrum.03541-22] [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: 03/15/2023] Open
Abstract
Escherichia coli (E. coli), a Gram-negative bacterium, is an important pathogen that causes several mammalian diseases. The outer membrane components of E. coli, namely, lipopolysaccharide (LPS) and bacterial lipoprotein, can induce the host innate immune response through pattern recognition receptors (PRRs). However, the detailed roles of the E. coli Braun lipoprotein (BLP) in the regulation of host inflammatory response to E. coli infection remain unclear. In this study, we sought to determine the effects of BLP on E. coli-induced host inflammatory response and lethality using mouse models. Experiments using the E. coli DH5α strain (BLP-positive), E. coli JE5505 strain (BLP-negative), and E. coli JE5505 strain combined with BLP indicated that the presence of BLP could alleviate mortality and organ (liver and lung) damage and decrease proinflammatory cytokine (tumor necrosis factor alpha [TNF-α] and interleukin-1β [IL-1β]) and chemokine (regulated on activation normal T-cell expressed and secreted [RANTES]) production in mouse serum and organs. Conversely, E. coli JE5505, E. coli DH5α strain, and E. coli JE5505 combined with BLP treatment induce enhanced anti-inflammatory cytokine (interleukin 10 [IL-10]) production in mouse serum and organs. In addition, BLP could regulate the secretion of proinflammatory cytokines (TNF-α and IL-1β), chemokines (RANTES), and anti-inflammatory factors (IL-10) through mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) signaling pathways in macrophages. Altogether, our results demonstrate that the bacterial component BLP plays crucial and protective roles in E. coli-infected mice, which may influence the outcome of inflammation in host response to E. coli infection. IMPORTANCE In this study, we investigated the roles of bacterial outer membrane component BLP in regulating inflammatory responses and lethality in mice that were induced by a ubiquitous and serious pathogen, Escherichia coli. BLP could alleviate the mortality of mice and organ damage, as well as decrease proinflammatory cytokines and chemokine production and enhance anti-inflammatory cytokine production in mouse serum and organs. Overall, our results demonstrate that the bacterial component BLP plays crucial and protective roles in E. coli-infected mice through regulating the production of an inflammatory mediator, which may influence the outcome of inflammation in host response to E. coli infection. Our findings provide new information about the basic biology involved in immune responses to E. coli and host-bacterial interactions, which have the potential to translate into novel approaches for the diagnosis and treatment of E. coli-related medical conditions, such as bacteremia and sepsis.
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Chang C, Cai R, Wu Q, Su Q. Uncovering the Genetic Link between Acute Myocardial Infarction and Ulcerative Colitis Co-Morbidity through a Systems Biology Approach. CARDIOVASCULAR INNOVATIONS AND APPLICATIONS 2023; 8. [DOI: 10.15212/cvia.2023.0034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Background: Cardiovascular diseases, particularly acute myocardial infarction, are the leading cause of disability and death. Atherosclerosis, the pathological basis of AMI, can be accelerated by chronic inflammation. Ulcerative colitis (UC), a chronic inflammatory disease associated with immunity, contributes to the risk of AMI development. However, controversy continues to surround the relationship between these two diseases. The present study unravels the pathogenesis of AMI and UC, to provide a new perspective on the clinical management of patients with these comorbidities.
Methods: Microarray datasets GSE66360 and GSE87473 were downloaded from the Gene Expression Omnibus database. Common differentially expressed genes (co-DEGs) between AMI and UC were identified, and the following analyses were performed: enrichment analysis, protein-protein interaction network construction, hub gene identification and co-expression analysis.
Results: A total of 267 co-DEGs (233 upregulated and 34 downregulated) were screened for further analysis. GO enrichment analysis suggested important roles of chemokines and cytokines in AMI and UC. In addition, the lipopolysaccharide-mediated signaling pathway was found to be closely associated with both diseases. KEGG enrichment analysis revealed that lipid and atherosclerosis, NF-κB, TNF and IL-17 signaling pathways are the core mechanisms involved in the progression of both diseases. Finally, 11 hub genes were identified with cytoHubba: TNF, IL1B, TLR2, CXCL8, STAT3, MMP9, ITGAX, CCL4, CSF1R, ICAM1 and CXCL1.
Conclusion: This study reveals a co-pathogenesis mechanism of AMI and UC regulated by specific hub genes, thus providing ideas for further mechanistic studies, and new perspectives on the clinical management of patients with these comorbidities.
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Li D, Liu L, Du X, Ma W, Zhang J, Piao W. MiRNA-374b-5p and miRNA-106a-5p are related to inflammatory bowel disease via regulating IL-10 and STAT3 signaling pathways. BMC Gastroenterol 2022; 22:492. [DOI: 10.1186/s12876-022-02533-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 10/07/2022] [Indexed: 11/29/2022] Open
Abstract
Abstract
Background
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is one of the most frequent gastrointestinal disorders worldwide. Although the actual etiology of IBD remains unclear, growing evidence suggests that CD4+ T cells-associated cytokines, including interferon (IFN)-γ, interleukin (IL)-10 and IL-17A, are crucial for the occurrence of IBD. It has been reported that there is a positive association between miRNAs and IBD development. In this study, we investigated the roles of hsa-miRNA-374b-5p(miRNA-374b-5p) and hsa-miRNA-106a-5p(miRNA-106a-5p) in regulating IBD development.
Methods
Serum was obtained from vein blood of IBD patients and healthy controls, qRT-PCR was performed to study the expression of miRNA-374b-5p and miRNA-106a-5p. Furthermore, we investigate the effects of overexpression or inhibition of miRNA-374b-5p on naïve CD4 + T cell subsets differentiation from vein blood of healthy controls by RT-qPCR, flow cytometry and western blot. And more the prediction and confirmation of the targeting genes of miRNA-374b-5p and miRNA-106a-5p were performed by bioinformatics softwares and dual-luciferase reporter assay.
Results
The results showed that miRNA-106a-5p and miRNA-374b-5p were significantly overexpressed in IBD patients. MiRNA-374b-5p could enhance Th1/Th17 cell differentiation and was related to IBD pathogenesis. MiRNA-374b-5p overexpression induced the mRNA expression of IL-17A and IFN-γ, and suppressed that of IL-10 in T cells. MiRNA-374b-5p inhibition decreased the mRNA expression of IL-17A and IFN-γ, while upregulated that of IL-10 in T cells. These qPCR data were further verified at protein level by western blotting and flow cytometry. In addition, dual-luciferase reporter (DLR) assay indicated that miRNA-374b-5p was directly targeted by IL-10, a key anti-inflammatory cytokine for preventing the occurrence of IBD. Meanwhile, STAT3 was identified as a target gene of miRNA-106a-5p by DLR assays. Further analysis revealed that miRNA-374b-5p regulated JAK1 and STAT3 pathways in CD4+ T cells via IL-10/STAT3 axis. MiRNA-374b-5p overexpression remarkably decreased the mRNA expression and phosphorylated (ser-727) protein levels of STAT3, while miRNA-374b-5p inhibition had the opposite effects.
Conclusion
MiRNA-374b-5p and miRNA-106a-5p may contribute to IBD development by regulating IL-10/STAT3 signal transduction.
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24
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Liu C, Wang S, Xiang Z, Xu T, He M, Xue Q, Song H, Gao P, Cong Z. The chemistry and efficacy benefits of polysaccharides from Atractylodes macrocephala Koidz. Front Pharmacol 2022; 13:952061. [PMID: 36091757 PMCID: PMC9452894 DOI: 10.3389/fphar.2022.952061] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/21/2022] [Indexed: 11/17/2022] Open
Abstract
Atractylodes macrocephala Koidz (AM), traditional Chinese medicine (TCM) with many medicinal values, has a long usage history in China and other oriental countries. The phytochemical investigation revealed the presence of volatile oils, polysaccharides, lactones, flavonoids, and others. The polysaccharides from AM are important medicinal components, mainly composed of glucose (Glc), galactose (Gal), rhamnose (Rha), arabinose (Ara), mannose (Man), galacturonic acid (GalA) and xylose (Xyl). It also showed valuable bioactivities, such as immunomodulatory, antitumour, gastroprotective and intestinal health-promoting, hepatoprotective, hypoglycaemic as well as other activities. At the same time, based on its special structure and pharmacological activity, it can also be used as immune adjuvant, natural plant supplement and vaccine adjuvant. The aim of this review is to summarize and critically analyze up-to-data on the chemical compositions, biological activities and applications of polysaccharide from AM based on scientific literatures in recent years.
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Affiliation(s)
- Congying Liu
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shengguang Wang
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zedong Xiang
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tong Xu
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Mengyuan He
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qing Xue
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Huaying Song
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Peng Gao
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- *Correspondence: Peng Gao, ; Zhufeng Cong,
| | - Zhufeng Cong
- Shandong First Medical University Affiliated Shandong Tumor Hospital and Institute, Shandong Cancer Hospital and Institute, Jinan, China
- *Correspondence: Peng Gao, ; Zhufeng Cong,
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Que W, Ma K, Hu X, Guo WZ, Li XK. Combinations of anti-GITR antibody and CD28 superagonist induce permanent allograft acceptance by generating type 1 regulatory T cells. SCIENCE ADVANCES 2022; 8:eabo4413. [PMID: 35921418 PMCID: PMC9348800 DOI: 10.1126/sciadv.abo4413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 06/21/2022] [Indexed: 06/15/2023]
Abstract
Type 1 regulatory T (Tr1) cells represent a subset of IL-10-producing CD4+Foxp3- T cells and play key roles in promoting transplant tolerance. However, no effective pharmacological approaches have been able to induce Tr1 cells in vivo. We herein report the combined use of a CD28 superagonist (D665) and anti-glucocorticoid-induced tumor necrosis factor receptor-related protein monoclonal antibody (G3c) to induce Tr1 cells in vivo. Large amounts of IL-10/interferon-γ-co-producing CD4+Foxp3- Tr1 cells were generated by D665-G3c sequential treatment in mice. Mechanistic studies suggested that D665-G3c induced Tr1 cells via transcription factors Prdm1 and Maf. G3c contributed to Tr1 cell generation via the activation of mitogen-activated protein kinase-signal transducer and activator of transcription 3 signaling. Tr1 cells suppressed dendritic cell maturation and T cell responses and mediated permanent allograft acceptance in fully major histocompatibility complex-mismatched mice in an IL-10-dependent manner. In vivo Tr1 cell induction is a promising strategy for achieving transplant tolerance.
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Affiliation(s)
- Weitao Que
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kuai Ma
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Xin Hu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Wen-Zhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiao-Kang Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
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Zhang XY, Shen HH, Qin XY, Wang CJ, Hu WT, Liu SP, Wu JN, Xie F, Xu FY, Zhao SM, Yuan YY, Li MQ. IL-27 promotes decidualization via the STAT3-ESR/PGR regulatory axis. J Reprod Immunol 2022; 151:103623. [PMID: 35430461 DOI: 10.1016/j.jri.2022.103623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/15/2022] [Accepted: 04/08/2022] [Indexed: 01/18/2023]
Abstract
Appropriate decidualization is of great importance for embryo implantation, placental development and successful pregnancy. Although it has been well-acknowledged that decidualization relies on activation of progesterone-mediated signaling pathway, the exact mechanisms have not been elucidated. Here, we demonstrated that both IL-27 and IL27RA were highly expressed in decidua than those in endometrium during secretory phase. Estrogen plus progesterone significantly upregulated the expression of IL-27 and IL-27RA in endometrium stromal cells (ESCs). In addition, inhibiting IL-27 signaling with IL-27 neutralization antibody (anti-IL-27) suppressed the expression of decidualization-related molecules, receptors of estrogen (gene coded by ESR) and progesterone (PGR) induced by cAMP or estrogen plus progesterone. Similar results were obtained from Il27ra-/- (knockout of Il27ra) female mice. Moreover, knockout of Il27ra did not affect the estrus cycle and folliculogenesis in mice but reduced implantation rate with the impairing decidualization. Mechanistically, IL-27 upregulated the expression of ESR1, ESR2 and PGR in ESCs and DSCs, as well as the phosphorylation level of STAT3. In the presence of estrogen plus progesterone, treatment with ESCs with anti-IL-27 inhibited the activation of STAT3. Also, the expression of ESR, PGR was decreased in Il27ra-/- mice. In conclusion, these findings demonstrate that IL-27 upregulated by estrogen and progestogen promotes decidualization possibly through a STAT3-dominant pathway.
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Affiliation(s)
- Xin-Yan Zhang
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China; NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 201203, People's Republic of China
| | - Hui-Hui Shen
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China
| | - Xue-Yun Qin
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China
| | - Cheng-Jie Wang
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China
| | - Wen-Ting Hu
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China
| | - Song-Ping Liu
- Department of Obstetrics and Gynecology, Jinshan Hospital of Fudan University, Shanghai 201508, People's Republic of China
| | - Jiang-Nan Wu
- Clinical Epidemiology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, People's Republic of China
| | - Feng Xie
- Center for Diagnosis and Treatment of Cervical and Uterine Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China
| | - Feng-Yuan Xu
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Shi-Min Zhao
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China.
| | - Yi-Yuan Yuan
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China; NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 201203, People's Republic of China; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China.
| | - Ming-Qing Li
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China; NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 201203, People's Republic of China; Department of Obstetrics and Gynecology, Jinshan Hospital of Fudan University, Shanghai 201508, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China.
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27
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Yan S, Zhang C, Ji X, Wu G, Huang X, Zhang Y, Zhang Y. MSC-ACE2 Ameliorates Streptococcus uberis-Induced Inflammatory Injury in Mammary Epithelial Cells by Upregulating the IL-10/STAT3/SOCS3 Pathway. Front Immunol 2022; 13:870780. [PMID: 35677060 PMCID: PMC9167935 DOI: 10.3389/fimmu.2022.870780] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
In the dairy industry, Streptococcus uberis (S. uberis) is one of the most important pathogenic bacteria associated with mastitis in milk-producing cows, causing vast economic loss. To date, the only real effective method of treating and preventing streptococcal mastitis is antimicrobial therapy. In many inflammatory diseases, mesenchymal stem cells (MSCs) and angiotensin-converting enzyme 2 (ACE2) play an anti-inflammatory and anti-injurious role. Accordingly, we hypothesized that MSCs overexpressing ACE2 (MSC-ACE2) would ameliorate the inflammatory injury caused by S. uberis in mammary epithelial cells more efficiently than MSC alone. By activating the transcription 3/suppressor of cytokine signaling 3 (IL-10/STAT3/SOCS3) signaling pathway, MSC-ACE2 inhibited the NF-κB, MAPKs, apoptosis, and pyroptosis passways. Moreover, MSC-ACE2 overturned the downregulation of Occludin, Zonula occludens 1 (ZO-1), and Claudin-3 expression levels caused by S. uberis, suggesting that MSC-ACE2 promotes the repair of the blood-milk barrier. MSC-ACE2 demonstrated greater effectiveness than MSC alone, as expected. Based on these results, MSC-ACE2 effectively inhibits EpH4-Ev cell's inflammatory responses induced by S. uberis, and would be an effective therapeutic tool for treating streptococcal mastitis.
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Affiliation(s)
| | | | | | | | | | | | - Yuanshu Zhang
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
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Hiraoka T, Hirota Y, Aikawa S, Iida R, Ishizawa C, Kaku T, Hirata T, Fukui Y, Akaeda S, Matsuo M, Shimizu-Hirota R, Takeda N, Osuga Y. Constant Activation of STAT3 Contributes to the Development of Adenomyosis in Females. Endocrinology 2022; 163:6563397. [PMID: 35380652 DOI: 10.1210/endocr/bqac044] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Indexed: 11/19/2022]
Abstract
Adenomyosis is a benign uterine disease that causes dysmenorrhea, heavy menstrual bleeding, and infertility; however, its pathophysiology remains unclear. Since signal transducer and activator of transcription 3 (STAT3) is crucial for endometrial regeneration, we hypothesized that STAT3 participates in adenomyosis pathophysiology. To investigate the influence of STAT3 on adenomyosis development, this study was performed using a novel mouse model of adenomyosis and human specimens of eutopic endometria and adenomyosis lesions. We established a novel mouse model of adenomyosis by puncturing entire mouse uterine layers with a thin needle. Mouse eutopic and ectopic endometria showed a positive immunoreactivity for phosphorylated STAT3 (pSTAT3), the active form of STAT3. Decreased numbers of adenomyotic lesions and reduced expression of Cxcl1, Icam1, and Spp1, which are associated with immune cell chemotaxis and tissue regeneration, were observed in uterine Stat3-deficient mice compared with the controls. In humans, pSTAT3 was intensely expressed at both the eutopic endometrium and the adenomyotic lesions regardless of the menstrual cycle phases. Conversely, it was limitedly expressed in the eutopic endometrium during the menstrual and proliferative phases in women without adenomyosis. Our findings indicate that continuous STAT3 activation promotes adenomyosis development. STAT3 inhibition can be a promising treatment strategy in patients with adenomyosis.
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Affiliation(s)
- Takehiro Hiraoka
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yasushi Hirota
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shizu Aikawa
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Rei Iida
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Chihiro Ishizawa
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuaki Kaku
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomoyuki Hirata
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yamato Fukui
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shun Akaeda
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mitsunori Matsuo
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryoko Shimizu-Hirota
- Department of Internal Medicine, Center for Preventive Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Norihiko Takeda
- Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Wen Z, Aleem MT, Aimulajiang K, Chen C, Liang M, Song X, Xu L, Li X, Yan R. The GT1-TPS Structural Domain Protein From Haemonchus contortus Could Be Suppressive Antigen of Goat PBMCs. Front Immunol 2022; 12:787091. [PMID: 35058927 PMCID: PMC8764253 DOI: 10.3389/fimmu.2021.787091] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/08/2021] [Indexed: 12/15/2022] Open
Abstract
Trehalose phosphate synthase (TPS), a key enzyme in trehalose synthesis, is not present in mammals but critical to the viability of a wide range of lower organisms. However, almost nothing is known about the function of Hc-TPS (GT1-TPS structural domain protein from Haemonchus contortus). In this study, Hc-TPS gene was cloned and the recombinant protein (rHc-TPS) was expressed and purified. The quantitative real-time PCR (qPCR) results showed that Hc-TPS was transcribed at different stages of H. contortus, with higher levels of transcription at the molting and embryo stages. Immunofluorescence analysis showed that Hc-TPS was widely distributed in adults, but the expression was mainly localized on the mucosal surface of the intestine as well as in the embryos of female worms. The impacts of rHc-TPS on peripheral blood mononuclear cell (PBMC) proliferation, nitric oxide (NO) generation, transcriptional expression of cytokines, and related pathways were examined by co-incubating rHc-TPS with goat PBMCs. The results showed that rHc-TPS significantly inhibited PBMC proliferation and NO secretion in a dose-dependent manner. We also found that rHc-TPS activated the interleukin (IL)-10/signal transducer and activator of transcription 3/suppressor of cytokine signaling 3 (IL-10/STAT3/SOCS3) axis and significantly promoted SOCS3 expression, while inhibiting interferon-gamma (INF-γ), IL-4, IL-9, and IL-2 pathways. Our findings may contribute to understanding the immune evasion mechanism for the parasite during host-parasite interactions and also help to provide ideas for discovering new drug targets.
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Affiliation(s)
- Zhaohai Wen
- Ministry of Education (MOE) Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Muhammad Tahir Aleem
- Ministry of Education (MOE) Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Kalibixiati Aimulajiang
- Ministry of Education (MOE) Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.,State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, China
| | - Cheng Chen
- Ministry of Education (MOE) Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Meng Liang
- Ministry of Education (MOE) Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Xiaokai Song
- Ministry of Education (MOE) Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Lixin Xu
- Ministry of Education (MOE) Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Xiangrui Li
- Ministry of Education (MOE) Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Ruofeng Yan
- Ministry of Education (MOE) Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
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30
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Jin K, Parreau S, Warrington KJ, Koster MJ, Berry GJ, Goronzy JJ, Weyand CM. Regulatory T Cells in Autoimmune Vasculitis. Front Immunol 2022; 13:844300. [PMID: 35296082 PMCID: PMC8918523 DOI: 10.3389/fimmu.2022.844300] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/28/2022] [Indexed: 12/14/2022] Open
Abstract
Blood vessels are indispensable for host survival and are protected from inappropriate inflammation by immune privilege. This protection is lost in patients with autoimmune vasculitides, a heterogeneous group of diseases causing damage to arteries, arterioles, and capillaries. Vasculitis leads to vascular wall destruction and/or luminal occlusion, resulting in hemorrhage and tissue ischemia. Failure in the quantity and quality of immunosuppressive regulatory T cells (Treg) has been implicated in the breakdown of the vascular immune privilege. Emerging data suggest that Treg deficiencies are disease-specific, affecting distinct pathways in distinct vasculitides. Mechanistic studies have identified faulty CD8+ Tregs in Giant Cell Arteritis (GCA), a vasculitis of the aorta and the large aortic branch vessels. Specifically, aberrant signaling through the NOTCH4 receptor expressed on CD8+ Treg cells leads to rerouting of intracellular vesicle trafficking and failure in the release of immunosuppressive exosomes, ultimately boosting inflammatory attack to medium and large arteries. In Kawasaki’s disease, a medium vessel vasculitis targeting the coronary arteries, aberrant expression of miR-155 and dysregulated STAT5 signaling have been implicated in undermining CD4+ Treg function. Explorations of mechanisms leading to insufficient immunosuppression and uncontrolled vascular inflammation hold the promise to discover novel therapeutic interventions that could potentially restore the immune privilege of blood vessels and pave the way for urgently needed innovations in vasculitis management.
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Affiliation(s)
- Ke Jin
- Department of Medicine, Mayo College of Medicine and Science, Rochester, MN, United States
| | - Simon Parreau
- Department of Medicine, Mayo College of Medicine and Science, Rochester, MN, United States
| | - Kenneth J. Warrington
- Department of Medicine, Mayo College of Medicine and Science, Rochester, MN, United States
| | - Matthew J. Koster
- Department of Medicine, Mayo College of Medicine and Science, Rochester, MN, United States
| | - Gerald J. Berry
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States
| | - Jörg J. Goronzy
- Department of Medicine, Mayo College of Medicine and Science, Rochester, MN, United States
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Cornelia M. Weyand
- Department of Medicine, Mayo College of Medicine and Science, Rochester, MN, United States
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
- *Correspondence: Cornelia M. Weyand,
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31
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Zhu SY, Li CX, Tong YX, Xu YR, Wang ZY, Li JL. IL-6/STAT3/Foxo1 Axis as a Target of Lycopene Ameliorates Atrazine-Induced Thymic Mitophagy and Pyroptosis Cross-talk. Food Funct 2022; 13:8871-8879. [DOI: 10.1039/d2fo01497a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The intensive adoption of atrazine (ATZ) has been a persistently widespread pollutant in daily life. However, ATZ is still used as an essential herbicide in numerous countries because its toxic...
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32
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Wen Z, Xie X, Aleem MT, Aimulajiang K, Chen C, Liang M, Song X, Xu L, Li X, Yan R. In vitro characterization of Haemonchus contortus trehalose-6-phosphate phosphatase and its immunomodulatory effects on peripheral blood mononuclear cells (PBMCs). Parasit Vectors 2021; 14:611. [PMID: 34930417 PMCID: PMC8685816 DOI: 10.1186/s13071-021-05115-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/04/2021] [Indexed: 12/15/2022] Open
Abstract
Background Trehalose-6-phosphate phosphatase (TPP6) is a key enzyme in the trehalose biosynthesis pathway. The accumulation of TPP6 inside the body is harmful to the pathogen, but almost nothing is currently known about the function of TPP6 from Haemonchus contortus (CRE-GOB-1). Methods The H. contortus CRE-GOB-1 (HcGOB) gene was cloned and recombinant protein of GOB (rHcGOB) was expressed; transcription of the HcGOB gene at different developmental stages of H. contortus was then studied. The spatial expression pattern of the HcGOB gene in adult female and male worms was determined by both quantitative real-time PCR (qPCR) and immunofluorescence. The binding of the rHcGOB protein to goat PBMCs was assessed by immunofluorescence assay. The immunomodulatory impacts of rHcGOB on cell proliferation, nitric oxide generation and cytokine secretion were assessed by co-culture of rHcGOB protein with goat PBMCs. Results The HcGOB protein was transcribed in eggs, infective third-stage larvae (iL3s) and adults of H. contortus, with the highest transcript levels found in the egg stage. The transcript levels were significantly elevated in iL3s after manual desheathing. HcGOB was widely distributed in adult worms where it was mainly localized in the gut and gonads. rHcGOB was observed to bind to PBMCs and also to be recognized by sera collected from a goat infected with H. contortus. rHcGOB significantly activated the interleukin-10/transforming growth factor β/signal transducer and activator of transcription 3 (IL-10/TGF-β/STAT3) pathway in PBMCs while suppressing the transcription and expression of IL-4 and IL-17. Conclusions These results suggest that the HcGOB gene plays an important role in the development, parasitism and reproduction of H. contortus. The rHcGOB protein affected the immunomodulatory function of PBMCs in the in vitro study, suggesting that this protein would be a promising vaccine target. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13071-021-05115-4.
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Affiliation(s)
- ZhaoHai Wen
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - XinRan Xie
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Muhammad Tahir Aleem
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Kalibixiati Aimulajiang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China.,State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, 830011, Xinjiang, People's Republic of China
| | - Cheng Chen
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Meng Liang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - XiaoKai Song
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - LiXin Xu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - XiangRui Li
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - RuoFeng Yan
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China.
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33
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Carreras J, Kikuti YY, Hiraiwa S, Miyaoka M, Tomita S, Ikoma H, Ito A, Kondo Y, Itoh J, Roncador G, Martinez A, Colomo L, Hamoudi R, Ando K, Nakamura N. High PTX3 expression is associated with a poor prognosis in diffuse large B-cell lymphoma. Cancer Sci 2021; 113:334-348. [PMID: 34706126 PMCID: PMC8748251 DOI: 10.1111/cas.15179] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 12/02/2022] Open
Abstract
Tumor‐associated macrophages (TAMs) are associated with a poor prognosis of diffuse large B‐cell lymphoma (DLBCL). As macrophages are heterogeneous, the immune polarization and their pathological role warrant further study. We characterized the microenvironment of DLBCL by immunohistochemistry in a training set of 132 cases, which included 10 Epstein–Barr virus‐encoded small RNA (EBER)‐positive and five high‐grade B‐cell lymphomas, with gene expression profiling in a representative subset of 37 cases. Diffuse large B‐cell lymphoma had a differential infiltration of TAMs. The high infiltration of CD68 (pan‐macrophages), CD16 (M1‐like), CD163, pentraxin 3 (PTX3), and interleukin (IL)‐10‐positive macrophages (M2c‐like) and low infiltration of FOXP3‐positive regulatory T lymphocytes (Tregs) correlated with poor survival. Activated B cell‐like DLBCL was associated with high CD16, CD163, PTX3, and IL‐10, and EBER‐positive DLBCL with high CD163 and PTX3. Programmed cell death‐ligand 1 positively correlated with CD16, CD163, IL‐10, and RGS1. In a multivariate analysis of overall survival, PTX3 and International Prognostic Index were identified as the most relevant variables. The gene expression analysis showed upregulation of genes involved in innate and adaptive immune responses and macrophage and Toll‐like receptor pathways in high PTX3 cases. The prognostic relevance of PTX3 was confirmed in a validation set of 159 cases. Finally, in a series from Europe and North America (GSE10846, R‐CHOP‐like treatment, n = 233) high gene expression of PTX3 correlated with poor survival, and moderately with CSF1R, CD16, MITF, CD163, MYC, and RGS1. Therefore, the high infiltration of M2c‐like immune regulatory macrophages and low infiltration of FOXP3‐positive Tregs is associated with a poor prognosis in DLBCL, for which PTX3 is a new prognostic biomarker.
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Affiliation(s)
- Joaquim Carreras
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Yara Yukie Kikuti
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Shinichiro Hiraiwa
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Masashi Miyaoka
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Sakura Tomita
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Haruka Ikoma
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Atsushi Ito
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Yusuke Kondo
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Johbu Itoh
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Giovanna Roncador
- Monoclonal Antibodies Core Unit, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain
| | - Antonio Martinez
- Department of Pathology, Hospital Clinic Barcelona, University of Barcelona, Institut d'investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Lluis Colomo
- Department of Pathology, Hospital del Mar, Institute Hospital del Mar d'Investigacions Mediques (IMIM), Barcelona, Spain
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Division of Surgery and Interventional Science, University College London, London, United Kingdom
| | - Kiyoshi Ando
- Department of Hematology and Oncology, Tokai University, School of Medicine, Isehara, Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
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Tan H, Su G, Tan X, Qin Y, Chen L, Yuan G, Kijlstra A, Yang P. SNP-mediated binding of TBX1 to the enhancer element of IL-10 reduces the risk of Behçet's disease. Epigenomics 2021; 13:1523-1537. [PMID: 34612069 DOI: 10.2217/epi-2021-0215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aims: The genetic association between Behçet's disease susceptibility and IL-10 has been confirmed in multiple cohorts, but the underlying mechanism of this association remains unclear. Materials & methods: We combined public resources and laboratory experiments (electrophoretic mobility shift assays, chromatin immunoprecipitation, luciferase reporter gene and CRISPR/Cas9 genome editing) to analyze transcription factor binding and enhancer activity controlling IL-10 expression. Results & conclusion: The T allele of noncoding rs3024490 within super-enhancer elements is able to specifically bind TBX1 and, in turn, promotes the enhancer activity and increased expression of IL-10. However, a relative deficiency in TBX1 in Behçet's disease patients leads to the low expression of IL-10 and increased risk of developing Behçet's disease.
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Affiliation(s)
- Handan Tan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, PR China
| | - Guannan Su
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, PR China
| | - Xiao Tan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, PR China
| | - Yang Qin
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, PR China
| | - Lin Chen
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, PR China
| | - Gangxiang Yuan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, PR China
| | - Aize Kijlstra
- University Eye Clinic Maastricht, Maastricht, Limburg, The Netherlands
| | - Peizeng Yang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, PR China
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35
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Hovhannisyan L, Czechowska E, Gutowska-Owsiak D. The Role of Non-Immune Cell-Derived Extracellular Vesicles in Allergy. Front Immunol 2021; 12:702381. [PMID: 34489951 PMCID: PMC8417238 DOI: 10.3389/fimmu.2021.702381] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/31/2021] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs), and especially exosomes, have been shown to mediate information exchange between distant cells; this process directly affects the biological characteristics and functionality of the recipient cell. As such, EVs significantly contribute to the shaping of immune responses in both physiology and disease states. While vesicles secreted by immune cells are often implicated in the allergic process, growing evidence indicates that EVs from non-immune cells, produced in the stroma or epithelia of the organs directly affected by inflammation may also play a significant role. In this review, we provide an overview of the mechanisms of allergy to which those EVs contribute, with a particular focus on small EVs (sEVs). Finally, we also give a clinical perspective regarding the utilization of the EV-mediated communication route for the benefit of allergic patients.
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Affiliation(s)
- Lilit Hovhannisyan
- University of Gdansk, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Gdansk, Poland
- Department of in vitro Studies, Institute of Biotechnology and Molecular Medicine, Gdansk, Poland
| | - Ewa Czechowska
- University of Gdansk, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Gdansk, Poland
| | - Danuta Gutowska-Owsiak
- University of Gdansk, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Gdansk, Poland
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
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Guo HH, Jing XY, Chen H, Xu HX, Zhu BM. STAT3 but Not STAT5 Contributes to the Protective Effect of Electroacupuncture Against Myocardial Ischemia/Reperfusion Injury in Mice. Front Med (Lausanne) 2021; 8:649654. [PMID: 34307396 PMCID: PMC8299366 DOI: 10.3389/fmed.2021.649654] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/13/2021] [Indexed: 02/05/2023] Open
Abstract
Electroacupuncture (EA) can help reduce infarct size and injury resulting from myocardial ischemia/reperfusion (I/R); however, the underlying molecular mechanism remains unknown. We previously reported that STAT5 plays a critical role in the cardioprotective effect of remote ischemic preconditioning (RIPC). Here, we assessed the effects of electroacupuncture pretreatment (EAP) on myocardial I/R injury in the presence and/or absence of Stat5 in mice and investigated whether EAP exerts its cardioprotective effects in a STAT5-dependent manner. Adult Stat5fl/fl and Stat5-cKO mice were exposed to EAP at Neiguan (PC6) for 7 days before the induction of I/R injury by left anterior descending (LAD) coronary artery ligation. The myocardial infarct size (IS), area at risk, and apoptotic rate of cardiomyocytes were detected. RT-qPCR and western blotting were used to measure gene and protein expression, respectively, in homogenized heart tissues. RNA-seq was used to identify candidate genes and pathways. Our results showed that EAP decreased IS and the rate of cardiomyocyte apoptosis. We further found that STAT5 was activated by EAP in Stat5fl/fl mice but not in Stat5-cKO mice, whereas the opposite was observed for STAT3. Following EAP, the levels of the antiapoptotic proteins Bcl-xL, Bcl-2, and p-AKT were increased in the presence of Stat5, while that of interleukin 10 (IL-10) was increased in both Stat5fl/fl and Stat5-cKO. The gene expression profile in heart tissues was different between Stat5fl/fl and the Stat5-cKO mice with EAP. Importantly, the top 30 DEGs under EAP in the Stat5-cKO mice were enriched in the IL-6/STAT3 signaling pathway. Our results revealed for the first time that the protective effect of EAP following myocardial I/R injury was attributable to, but not dependent on, STAT5. Additionally, we found that EAP could activate STAT3 signaling in the absence of the Stat5 gene, and could also activate antiapoptotic, survival, and anti-inflammatory signaling pathways.
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Affiliation(s)
- Hui-Hui Guo
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xin-Yue Jing
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hui Chen
- Rehabilitation Medicine Department, YE DA Hospital of Yantai, Yantai, China
| | - Hou-Xi Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China
| | - Bing-Mei Zhu
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
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Pan L, Wang J, Liu J, Guo L, Yang S. Deficiency in the frequency and function of Tr1 cells in IgAV and the possible role of IL-27. Rheumatology (Oxford) 2021; 60:3432-3442. [PMID: 33280050 PMCID: PMC8516516 DOI: 10.1093/rheumatology/keaa752] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 10/01/2020] [Indexed: 12/14/2022] Open
Abstract
Objective Type 1 regulatory T (Tr1) cells are involved in the pathogenesis of numerous immune-mediated diseases. However, little is known about whether and how Tr1 cells affect the development of IgA vasculitis (IgAV). We aimed to investigate this question in IgAV patients. Methods . Tr1 cells in peripheral blood and kidney tissue of IgAV patients were analysed by multi-parametric flow cytometry and immunofluorescence techniques. An in vitro assay of suppression of T cell proliferation and cytokine release was performed to evaluate the function of Tr1 cells. Real-time PCR and cell stimulation in vitro were used to explore the roles of IL-27 and early growth response gene 2 (EGR2). Results The frequency of Tr1 cells was decreased in peripheral blood but increased in kidney tissue from IgAV patients. A defective suppressive function of Tr1 cells in IgAV was observed. The frequency of Tr1 cells and the cytokines secreted by them were up-regulated in the presence of recombinant IL-27 in vitro. Moreover, IL-27 also increased the expression of EGR2. Furthermore, lower frequency of Tr1 cells during remission had a higher recurrence rate. Conclusion Tr1 cells are involved in the pathogenesis of IgAV. The low IL-27 in IgAV is responsible for impaired frequency and function of Tr1 cells, and EGR2 may be the specific transcription factor involved in the progression. Tr1 may be a risk factor for IgAV recurrence.
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Affiliation(s)
- Lu Pan
- Department of Pediatric Rheumatology and Allergy, The First Hospital of Jilin University, Changchun, China
| | - Jinghua Wang
- Department of Pediatric Rheumatology and Allergy, The First Hospital of Jilin University, Changchun, China
| | - Jinxiang Liu
- Department of Pediatric Rheumatology and Allergy, The First Hospital of Jilin University, Changchun, China
| | - Lishuang Guo
- Department of Pediatric Rheumatology and Allergy, The First Hospital of Jilin University, Changchun, China
| | - Sirui Yang
- Department of Pediatric Rheumatology and Allergy, The First Hospital of Jilin University, Changchun, China
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Sayitoglu EC, Freeborn RA, Roncarolo MG. The Yin and Yang of Type 1 Regulatory T Cells: From Discovery to Clinical Application. Front Immunol 2021; 12:693105. [PMID: 34177953 PMCID: PMC8222711 DOI: 10.3389/fimmu.2021.693105] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 05/24/2021] [Indexed: 12/23/2022] Open
Abstract
Regulatory T cells are essential players of peripheral tolerance and suppression of inflammatory immune responses. Type 1 regulatory T (Tr1) cells are FoxP3- regulatory T cells induced in the periphery under tolerogenic conditions. Tr1 cells are identified as LAG3+CD49b+ mature CD4+ T cells that promote peripheral tolerance through secretion of IL-10 and TGF-β in addition to exerting perforin- and granzyme B-mediated cytotoxicity against myeloid cells. After the initial challenges of isolation were overcome by surface marker identification, ex vivo expansion of antigen-specific Tr1 cells in the presence of tolerogenic dendritic cells (DCs) and IL-10 paved the way for their use in clinical trials. With one Tr1-enriched cell therapy product already in a Phase I clinical trial in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), Tr1 cell therapy demonstrates promising results so far in terms of efficacy and safety. In the current review, we identify developments in phenotypic and molecular characterization of Tr1 cells and discuss the potential of engineered Tr1-like cells for clinical applications of Tr1 cell therapies. More than 3 decades after their initial discovery, Tr1 cell therapy is now being used to prevent graft versus host disease (GvHD) in allo-HSCT and will be an alternative to immunosuppression to promote graft tolerance in solid organ transplantation in the near future.
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Affiliation(s)
- Ece Canan Sayitoglu
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, United States
| | - Robert Arthur Freeborn
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, United States
| | - Maria Grazia Roncarolo
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, United States.,Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford School of Medicine, Stanford, CA, United States.,Center for Definitive and Curative Medicine (CDCM), Stanford School of Medicine, Stanford, CA, United States
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Li Z, Wang C, Mao Y, Cui J, Wang X, Dang J, Wang S. The expression of STAT3 inhibited the NF-ΚB signalling pathway and reduced inflammatory responses in mice with viral myocarditis. Int Immunopharmacol 2021; 95:107534. [PMID: 33752081 DOI: 10.1016/j.intimp.2021.107534] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/09/2021] [Accepted: 02/23/2021] [Indexed: 01/16/2023]
Abstract
BACKGROUND The aim of this study was to investigate the mechanism of STAT3 in reducing the inflammatory responses in mice with viral myocarditis (VMC). METHODS Induce and generate viral myocarditis by using coxsackievirus B3 (CVB3) infected cardiomyocyte-specific STAT3 conditional knockout (STAT3cKO) mice and BALB/c mice. Use RT-PCR and western blot techniques to detect the expression of related cytokines in the uninfected wild-type mice group (Control group), myocarditis wild-type mice group (Model group) and STAT3cKO group, as well as the differentiation of spleen T cells in each group. Eukaryotic expression plasmid pcDNA3-STAT3 can reduce the expression of inflammatory factors the in vitro cultured cardiomyocytes of the STAT3cKO group. RESULTS RT-PCR showed that compared with the Control group, the expression levels of VMC-related genes (NF-κB, TNF‑α, IL-1β and IL-1) and anti-inflammation-related cytokines (IL-10 and TGF-β) in the Model group went up (*p < 0.05, **p < 0.01, ***p < 0.001); and also compared with the Control group, the rise in the expression levels of the above VMC-related genes in the STAT3cKO group was particularly significant (***p < 0.001, ****p < 0.0001) but there was no significant difference in the expression of IL-10 and TGF-β. After 4 weeks, a second RT-PCR showed that the expression of inflammation-related genes in the STAT3cKO group continued to be activated (***p < 0.001, ****p < 0.0001). Western blotting was performed to detect the expression of p65, a key protein of the NF-κB signalling pathway. The results showed that the p65 protein content was increased and the IL-10 protein content was decreased in the STAT3cKO group; the results of the T cell differentiation test showed that the T cell differentiation rate increased in the STAT3cKO group (**p < 0.01). Eukaryotic expression plasmid pcDNA3-STAT3 could reduce the expression of NF-κB, TNF-α, IL-1β and IL-17 (**p < 0.01). CONCLUSION The expression of STAT3 gene in VMC could to a certain extent inhibit the NF-κB signalling pathway and reduce the inflammatory responses of VMC.
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Affiliation(s)
- Zhihui Li
- Department of Internal Medicine-Cardiovascular, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450007, China
| | - Chenqiong Wang
- Department of Rheumatism Immunology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yun Mao
- Department of Internal Medicine-Cardiovascular, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jieke Cui
- Department of Blood Specialty, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xi Wang
- Department of Internal Medicine-Cardiovascular, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Juan Dang
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Shilei Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
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Wu W, Wu G, Cao D. Acteoside Presents Protective Effects on Cerebral Ischemia/reperfusion Injury Through Targeting CCL2, CXCL10, and ICAM1. Cell Biochem Biophys 2021; 79:301-310. [PMID: 33439460 DOI: 10.1007/s12013-020-00965-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2020] [Indexed: 11/26/2022]
Abstract
The objective of this study is to investigate the roles of acteoside (ACT) in cells with oxygen-glucose deprivation and reoxygenation (OGD/R)-induced injury and the underlying mechanisms. The differentially expressed genes (DEGs) in rats with middle cerebral artery occlusion were identified using GSE61616 data set. Kyoto Encyclopedia of Genes and Genomes pathway enrichment with the DEGs and the prediction of ACT's targets were conducted using The Comparative Toxicogenomics Database. The OGD/R model was established with bEnd.3 cells. Following that, bEnd.3 cells were treated by distinct concentrations of ACT and IL-10. The proliferation and apoptosis of cells were analyzed by cell counting kit-8 and flow cytometry assays, respectively. Western blot was used to check involved proteins. Herein, we identified CCL2, CXCL10, and ICAM1 as the targets of ACT, which were upregulated in tissues of MACO rats and cells with OGD/R-induced injury. ACT promoted the proliferation but reduce the apoptosis of cells with OGD/R-induced injury. Moreover, these effects of ACT were enhanced by IL-10. After being treated with ACT, IL-10, or ACT together with IL-10, the levels of CCL2, CXCL10, and ICAM1 were all decreased, whereas p-Stat3 was raised in cells with OGD/R-induced injury, while Stat3 expression presented no significant difference among groups. ACT protected cells against OGD/R-induced injury through regulating the IL-10/Stat3 signaling, indicating that ACT might be an effective therapy drug to lower cerebral ischemia/reperfusion injury.
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Affiliation(s)
- Weijiang Wu
- Department of Neurosurgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, PR China
| | - Gang Wu
- Department of Neurology, Binzhou People's Hospital, Binzhou, Shandong Province, PR China
| | - Deyan Cao
- The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, PR China.
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Lyu X, Li G, Qiao Q. Identification of an immune classification for cervical cancer and integrative analysis of multiomics data. J Transl Med 2021; 19:200. [PMID: 33971902 PMCID: PMC8111986 DOI: 10.1186/s12967-021-02845-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 04/18/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND To understand the molecular mechanisms of the antitumour response, we analysed the immune landscape of cervical cancer to identify novel immune molecular classes. METHODS We established a stable immune molecular classification using a nonnegative matrix factorization algorithm and validated the correlation in two validation sets of 249 samples. RESULTS Approximately 78% of cervical cancers (CCs) (228/293) were identified to show significant enrichment in immune cells (e.g., CD8 T cells and macrophages), a type I IFN response, enhanced cytolytic activity and high PDCD1, and these CCs were referred to as the "immune class". We further identified two subtypes of the immune class: active immune and exhausted subtypes. Although the active immune subtype was characterized by enrichment of IFN signatures and better survival, the exhausted subtype expressed activated stroma, a wound healing signature, enhanced M2 macrophages and absence of CD8 T cells and the TGF-β response signature. Integrative analysis of multiomics data identified EGFR, JUN, MYC, FN1 and SERPINE1 as key modulators of the tumour immune microenvironment and potential targets for combination therapies which was validated in two validation sets. CONCLUSIONS Our study introduces a novel immune classification that might predict ideal candidates to receive immunotherapy or specific combination therapies.
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Affiliation(s)
- Xintong Lyu
- Department of Radiation Oncology, First Hospital of China Medical University, Heping District, Shenyang,, Liaoning, China
| | - Guang Li
- Department of Radiation Oncology, First Hospital of China Medical University, Heping District, Shenyang,, Liaoning, China
| | - Qiao Qiao
- Department of Radiation Oncology, First Hospital of China Medical University, Heping District, Shenyang,, Liaoning, China.
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Ruan Z, Liang M, Shang L, Lai M, Deng X, Su X. Shikonin-mediated PD-L1 degradation suppresses immune evasion in pancreatic cancer by inhibiting NF-κB/STAT3 and NF-κB/CSN5 signaling pathways. Pancreatology 2021; 21:630-641. [PMID: 33707115 DOI: 10.1016/j.pan.2021.01.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) is a highly fatal malignancy with few effective therapies currently available. Recent studies have shown that PD-L1 inhibitors could be potential therapeutic targets for the treatment of PC. The present study aims to investigate the effect of Shikonin on immune evasion in PC with the involvement of the PD-L1 degradation. METHODS Initially, the expression patterns of PD-L1 and NF-κB in PC were predicted in-silico using the GEPIA database, and were subsequently validated using PC tissues. Thereafter, the correlation of NF-κB with STAT3, CSN5 and PD-L1 was examined. PC cells were treated with Shikonin, NF-κB inhibitor, STAT3 activator, and CSN5 overexpression plasmid to investigate effects on PD-L1 glycosylation and immune evasion in PC. Finally, in vivo tumor formation was induced in C57BL/6J mice, in order to verify the in vitro results. RESULTS PD-L1, NF-κB, NF-κB p65, STAT3, and CSN5 were highly expressed in PC samples, and NF-κB was positively correlated with STAT3/CSN5/PD-L1. Inhibition of NF-κB decreased PD-L1 glycosylation and increased PD-L1 degradation, whereas activated STAT3 and overexpressed CSN5 reversed these trends. Shikonin blocked immune evasion in PC, and lowered the expression of PD-L1, NF-κB, NF-κB p65, STAT3 and CSN5 in vivo and in vitro. CONCLUSION The findings indicated Shikonin inhibited immune evasion in PC by inhibiting PD-L1 glycosylation and activating the NF-κB/STAT3 and NF-κB/CSN5 signaling pathways. These effects of Shikonin on PC cells may bear important potential therapeutic implications for the treatment of PC.
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Affiliation(s)
- Zhiyan Ruan
- School of Pharmacy, Guangdong Food & Drug Vocational College, Guangzhou, 510520, PR China
| | - Minhua Liang
- School of Pharmacy, Guangdong Food & Drug Vocational College, Guangzhou, 510520, PR China
| | - Ling Shang
- School of Pharmacy, Guangdong Food & Drug Vocational College, Guangzhou, 510520, PR China
| | - Manxiang Lai
- School of Pharmacy, Guangdong Food & Drug Vocational College, Guangzhou, 510520, PR China
| | - Xiangliang Deng
- School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
| | - Xinguo Su
- School of Pharmacy, Guangdong Food & Drug Vocational College, Guangzhou, 510520, PR China.
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Sun H, Wu Y, Zhang Y, Ni B. IL-10-Producing ILCs: Molecular Mechanisms and Disease Relevance. Front Immunol 2021; 12:650200. [PMID: 33859642 PMCID: PMC8042445 DOI: 10.3389/fimmu.2021.650200] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 03/11/2021] [Indexed: 12/19/2022] Open
Abstract
Innate lymphoid cells (ILCs) are mainly composed of natural killer (NK) cells and helper-like lymphoid cells, which play a vital role in maintaining tissue homeostasis, enhancing adaptive immunity and regulating tissue inflammation. Alteration of the distribution and function of ILCs subgroups are closely related to the pathogenesis of inflammatory diseases and cancers. Interleukin-10 (IL-10) is a highly pleiotropic cytokine, and can be secreted by several cell types, among of which ILCs are recently verified to be a key source of IL-10. So far, the stable production of IL-10 can only be observed in certain NK subsets and ILC2s. Though the regulatory mechanisms for ILCs to produce IL-10 are pivotal for understanding ILCs and potential intervenes of diseases, which however is largely unknown yet. The published studies show that ILCs do not share exactly the same mechanisms for IL-10 production with helper T cells. In this review, the molecular mechanisms regulating IL-10 production in NK cells and ILC2s are discussed in details for the first time, and the role of IL-10-producing ILCs in diseases such as infections, allergies, and cancers are summarized.
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Affiliation(s)
- Hui Sun
- Department of Pathophysiology, Third Military Medical University, Chongqing, China
| | - Yuzhang Wu
- Chongqing International Institute for Immunology, Chongqing, China
| | - Yi Zhang
- Chongqing International Institute for Immunology, Chongqing, China
| | - Bing Ni
- Department of Pathophysiology, Third Military Medical University, Chongqing, China
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YQWY Decoction Improves Myocardial Remodeling via Activating the IL-10/Stat3 Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2020:7532892. [PMID: 33456490 PMCID: PMC7787750 DOI: 10.1155/2020/7532892] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 11/17/2022]
Abstract
Heart failure (HF) has been known as a global health problem, and cardiac remodeling plays an essential role in the development of HF. We hypothesized that YQWY decoction might exert a cardioprotective effect against myocardium inflammation, fibrosis, and apoptosis via activating the interleukin-10 (IL-10)/Stat3 signaling pathway. To test this hypothesis, the HF model in rats was established by pressure overload through the minimally invasive transverse aortic constriction (MTAC). Echocardiography was performed to assess the left ventricular function of rats. Myocardial fibrosis in rats was observed by Masson and Picrosirius red staining, and the degree of myocardial apoptosis was detected via TUNEL staining. In addition, expression levels of IL-10, tumor necrosis factor-α (TNF-α), Stat3 (P-Stat3), P65 (P-P65), CD68, collagen I, TGF-β, CTGF, Bax, Bcl-2, cleaved caspase-3, and PARP in rat serum and myocardium samples were examined by ELISA, western blot, and immunohistochemistry, respectively. YQWY decoction treatment significantly improved left ventricular function in HF rats, especially in those of the high-dose group (LVEF%: 51.29 ± 5.876 vs. 66.02 ± 1.264, P < 0.01;, LVFS%: 27.75 ± 3.757 vs. 37.76 ± 1.137, P < 0.01). Furthermore, YQWY decoction markedly inhibited MTAC-induced myocardial fibrosis as evidenced by downregulated collagen I, TGF-β, and CTGF in myocardium and alleviated apoptosis (downregulated caspase-3 and PARP and increased Bcl-2/Bax ratio in cardiomyocytes). In addition, YQWY decoction decreased the level of the proinflammatory cytokine TNF-α in both circulating blood and myocardium and attenuated infiltration of inflammatory cells in heart tissue from HF rats. Most importantly, YQWY decoction suppressed MTAC-induced NF-κB activation and phosphorylated Stat3 by upregulating IL-10 in rat heart tissues. Our study showed that YQWY decoction could attenuate MTAC-induced myocardial inflammation, fibrosis, apoptosis, and reverse the impairment of cardiac function in rats by activating the IL-10/Stat3 signaling pathway and improving myocardium remodeling. Our findings suggested a therapeutic potential of YQWY decoction in HF.
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Yan Y, Jiang X, Fu J, Huang J, Qiu Y, Ding D, Ge L, Zhang H, Huang L, Lu X, Hu Q. Immune responses and residual SARS-CoV-2 in two critically ill COVID-19 patients before and after lung transplantation. J Infect 2020; 82:84-123. [PMID: 33188798 PMCID: PMC7657937 DOI: 10.1016/j.jinf.2020.11.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 11/09/2020] [Indexed: 01/13/2023]
Affiliation(s)
- Yan Yan
- The International Joint Research Laboratory for Infection and Immunity (China-Germany), The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China; Center of Clinical Laboratory, The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xiufeng Jiang
- Department of Respiratory and Critical Care Medicine, The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Juanjuan Fu
- Department of Pathology, The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Jiehui Huang
- Department of Respiratory and Critical Care Medicine, The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yuanwang Qiu
- The International Joint Research Laboratory for Infection and Immunity (China-Germany), The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China; Department of Infectious Disease, The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Difei Ding
- Center of Clinical Laboratory, The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Lina Ge
- Center of Clinical Laboratory, The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Hao Zhang
- Department of Infectious Disease, The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Lihua Huang
- The International Joint Research Laboratory for Infection and Immunity (China-Germany), The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China; Department of Infectious Disease, The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China.
| | - Xiaojie Lu
- Department of Respiratory and Critical Care Medicine, The Fifth People's Hospital of Wuxi (Wuxi Infectious Disease Hospital), Affiliated Hospital of Jiangnan University, Wuxi, China; Department of Neurosurgery, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China.
| | - Qinxue Hu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China; Institute for Infection and Immunity, St. George's, University of London, London, United Kingdom.
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Impaired autophagy increases susceptibility to endotoxin-induced chronic pancreatitis. Cell Death Dis 2020; 11:889. [PMID: 33087696 PMCID: PMC7578033 DOI: 10.1038/s41419-020-03050-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 12/11/2022]
Abstract
Chronic pancreatitis (CP) is associated with elevated plasma levels of bacterial lipopolysaccharide (LPS) and we have demonstrated reduced acinar cell autophagy in human CP tissue. Therefore, we investigated the role of autophagy in experimental endotoxin-induced pancreatic injury and aimed to identify LPS in human CP tissue. Pancreatic Atg7-deficient mice were injected with a single sub-lethal dose of LPS. Expression of autophagy, apoptosis, necroptosis, and inflammatory markers was determined 3 and 24 h later utilizing immunoblotting and immunofluorescence. The presence of LPS in pancreatic tissue from mice and from patients and healthy controls was determined using immunohistochemistry, immunoblots, and chromogenic assay. Mice lacking pancreatic autophagy exhibited local signs of inflammation and were particularly sensitive to the toxic effect of LPS injection as compared to control mice. In response to LPS, Atg7Δpan mice exhibited enhanced vacuolization of pancreatic acinar cells, increase in TLR4 expression coupled to enhanced expression of NF-κΒ, JNK, and pro-inflammatory cytokines by acinar cells and enhanced infiltration by myeloid cells (but not Atg7F/F controls). Cell death was enhanced in Atg7Δpan pancreata, but only necroptosis and trypsin activation was further amplified following LPS injection along with elevated pancreatic LPS. The presence of LPS was identified in the pancreata from all 14 CP patients examined but was absent in the pancreata from all 10 normal controls. Altogether, these results support a potential role for metabolic endotoxemia in the pathogenesis of CP. Moreover, the evidence also supports the notion that autophagy plays a major cytoprotective and anti-inflammatory role in the pancreas, and blunting metabolic endotoxemia-induced CP.
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Xue W, Gao Y, Li Q, Lu Q, Bian Z, Tang L, Zeng Y, Chen C, Guo W. Immunomodulatory activity-guided isolation and characterization of a novel polysaccharide from Atractylodis macrocephalae Koidz. Int J Biol Macromol 2020; 161:514-524. [DOI: 10.1016/j.ijbiomac.2020.06.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 05/29/2020] [Accepted: 06/01/2020] [Indexed: 12/20/2022]
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Saha B, Bhattacharjee S, Sarkar A, Bhor R, Pai K, Bodhale N. Conundrums in leishmaniasis. Cytokine 2020; 145:155304. [PMID: 33004260 DOI: 10.1016/j.cyto.2020.155304] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 11/19/2022]
Abstract
Parasites of the genus Leishmania cause the disease leishmaniasis. As the sandfly vector transfers the promastigotes into the skin of the human host, the infection is either cured or exacerbated. In the process, there emerge several unsolved paradoxes of leishmaniasis. Chronologically, as the infections starts in skin, the role of the salivary proteins in supporting the infection or the host response to these proteins influencing the induction of immunological memory becomes a conundrum. As the parasite invokes inflammation, the infiltrating neutrophils may act as "Trojan Horse" to transfer parasites to macrophages that, along with dendritic cells, carry the parasite to lymphoid organs to start visceralization. As the visceralized infection becomes chronic, the acutely enhanced monocytopoiesis takes a downturn while neutropenia and thrombocytopenia ensue with concomitant rise in splenic colony-forming-units. These responses are accompanied by splenic and hepatic granulomas, polyclonal activation of B cells and deviation of T cell responses. The granuloma formation is both a containment process and a form of immunopathogenesis. The heterogeneity in neutrophils and macrophages contribute to both cure and progression of the disease. The differentiation of T-helper subsets presents another paradox of visceral leishmaniasis, as the counteractive T cell subsets influence the curing or non-curing outcome. Once the parasites are killed by chemotherapy, in some patients the cured visceral disease recurs as a cutaneous manifestation post-kala azar dermal leishmaniasis (PKDL). As no experimental model exists, the natural history of PKDL remains almost a black box at the end of the visceral disease.
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Affiliation(s)
- Baibaswata Saha
- Centre of Advanced Study, Department of Zoology, Savitribai Phule Pune University, Pune 411007, India
| | - Surajit Bhattacharjee
- Department of Molecular Biology and Bioinformatics, Tripura Central University, Agartala, India
| | - Arup Sarkar
- Trident Academy of Creative Technology, Bhubaneshwar, Odisha 751024, India
| | - Renuka Bhor
- Centre of Advanced Study, Department of Zoology, Savitribai Phule Pune University, Pune 411007, India
| | - Kalpana Pai
- Centre of Advanced Study, Department of Zoology, Savitribai Phule Pune University, Pune 411007, India
| | - Neelam Bodhale
- Jagadis Bose National Science Talent Search, 1300 Rajdanga Road, Kolkata 700107, India; National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
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Rada J, Donato M, Penas FN, Alba Soto C, Cevey ÁC, Pieralisi AV, Gelpi R, Mirkin GA, Goren NB. IL-10-Dependent and -Independent Mechanisms Are Involved in the Cardiac Pathology Modulation Mediated by Fenofibrate in an Experimental Model of Chagas Heart Disease. Front Immunol 2020; 11:572178. [PMID: 33072115 PMCID: PMC7541836 DOI: 10.3389/fimmu.2020.572178] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 09/02/2020] [Indexed: 12/12/2022] Open
Abstract
IL-10 is an anti-inflammatory cytokine that plays a significant role in the modulation of the immune response in many pathological conditions, including infectious diseases. Infection with Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas disease, results in an ongoing inflammatory response that may cause heart dysfunction, ultimately leading to heart failure. Given its infectious and inflammatory nature, in this work we analyzed whether the lack of IL-10 hinders the anti-inflammatory effects of fenofibrate, a PPARα ligand, in a murine model of Chagas heart disease (CHD) using IL-10 knockout (IL-10 KO) mice. Our results show fenofibrate was able to restore the abnormal cardiac function displayed by T. cruzi-infected mice lacking IL-10. Treatment with fenofibrate reduced creatine kinase (CK) levels in sera of IL-10 KO mice infected with T. cruzi. Moreover, although fenofibrate could not modulate the inflammatory infiltrates developing in the heart, it was able to reduce the increased collagen deposition in infected IL-10 KO mice. Regarding pro-inflammatory mediators, the most significant finding was the increase in serum IL-17. These were reduced in IL-10 KO mice upon fenofibrate treatment. In agreement with this, the expression of RORγt was reduced. Infection of IL-10 KO mice increased the expression of YmI, FIZZ and Mannose Receptor (tissue healing markers) that remained unchanged upon treatment with fenofibrate. In conclusion, our work emphasizes the role of anti-inflammatory mechanisms to ameliorate heart function in CHD and shows, for the first time, that fenofibrate attains this through IL-10-dependent and -independent mechanisms.
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Affiliation(s)
- Jimena Rada
- Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Martín Donato
- Departamento de Patología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Fisiopatología Cardiovascular, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Federico N Penas
- Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Catalina Alba Soto
- Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Investigaciones en Microbiología y Parasitología Médica, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ágata C Cevey
- Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Azul V Pieralisi
- Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ricardo Gelpi
- Departamento de Patología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Fisiopatología Cardiovascular, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Gerardo A Mirkin
- Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Investigaciones en Microbiología y Parasitología Médica, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Nora B Goren
- Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
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50
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Hiraoka T, Hirota Y, Fukui Y, Gebril M, Kaku T, Aikawa S, Hirata T, Akaeda S, Matsuo M, Haraguchi H, Saito-Kanatani M, Shimizu-Hirota R, Takeda N, Yoshino O, Fujii T, Osuga Y. Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment. Sci Rep 2020; 10:15523. [PMID: 32968170 PMCID: PMC7511330 DOI: 10.1038/s41598-020-72640-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
Although it has been reported that uterine signal transducer and activator of transcription 3 (STAT3) is essential for embryo implantation, the exact roles of uterine epithelial and stromal STAT3 on embryo implantation have not been elucidated. To address this issue, we generated Stat3-floxed/Ltf-iCre (Stat3-eKO), Stat3-floxed/Amhr2-Cre (Stat3-sKO), and Stat3-floxed/Pgr-Cre (Stat3-uKO) mice to delete Stat3 in uterine epithelium, uterine stroma, and whole uterine layers, respectively. We found that both epithelial and stromal STAT3 have critical roles in embryo attachment because all the Stat3-eKO and Stat3-sKO female mice were infertile due to implantation failure without any embryo attachment sites. Stat3-eKO uteri showed indented structure of uterine lumen, indicating the role of epithelial STAT3 in slit-like lumen formation in the peri-implantation uterus. Stat3-sKO uteri exhibited hyper-estrogenic responses and persistent cell proliferation of the epithelium in the peri-implantation uterus, suggesting the role of stromal STAT3 in uterine receptivity. In addition, Stat3-uKO female mice possessed not only the characteristic of persistent epithelial proliferation but also that of indented structure of uterine lumen. These findings indicate that epithelial STAT3 controls the formation of slit-like structure in uterine lumen and stromal STAT3 suppresses epithelial estrogenic responses and cell proliferation. Thus, epithelial and stromal STAT3 cooperatively controls uterine receptivity and embryo attachment through their different pathways.
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Affiliation(s)
- Takehiro Hiraoka
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.,Department of Obstetrics and Gynecology, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Yasushi Hirota
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. .,Frontier Outstanding Research for Clinical Empowerment (FORCE), Japan Agency for Medical Research and Development (AMED), Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Yamato Fukui
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Mona Gebril
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tetsuaki Kaku
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Shizu Aikawa
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tomoyuki Hirata
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Shun Akaeda
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Mitsunori Matsuo
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Hirofumi Haraguchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Mayuko Saito-Kanatani
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Ryoko Shimizu-Hirota
- Department of Internal Medicine, Center of Preventive Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
| | - Norihiko Takeda
- Center for Molecular Medicine, Jichi Medical University, Shimotuke, Tochigi, Japan
| | - Osamu Yoshino
- Department of Obstetrics and Gynecology, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Tomoyuki Fujii
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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