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Yasir M, Choe J, Hassan M, Kloczkowski A, Chun W. Recent advances and future perspectives in small molecule JAK2 inhibitors. Future Med Chem 2025:1-17. [PMID: 40392133 DOI: 10.1080/17568919.2025.2507564] [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: 03/28/2025] [Accepted: 05/08/2025] [Indexed: 05/22/2025] Open
Abstract
The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway is essential for controlling immune function, blood cell formation, and cell growth. Dysregulation of this pathway is implicated in various diseases, including hematologic malignancies, autoimmune disorders, and chronic inflammatory conditions. This review provides a comprehensive overview of the structural and functional aspects of JAK/STAT signaling, with a particular focus on the role of JAK2. This manuscript explores the primary regulators of the JAK/STAT pathway, such as Suppressors Of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS), and Protein Tyrosine Phosphatases (PTPs), which play a crucial role in maintaining cellular balance and stability. Additionally, the therapeutic landscape of JAK2 inhibitors is explored, covering both approved and investigational drugs, including their mechanisms of action, efficacy, and safety profiles. Emerging strategies such as drug repositioning using computational approaches and experimental validation are also highlighted. By integrating insights from molecular docking studies, machine learning models, and kinase assays, this review emphasizes the potential of JAK2 inhibitors in disease management.
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Affiliation(s)
- Muhammad Yasir
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | - Jongseon Choe
- Department of Microbiology and Immunology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | - Mubashir Hassan
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA
| | - Andrzej Kloczkowski
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA
| | - Wanjoo Chun
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
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Shi W, Hu J, Wang H, Zhong H, Zhang W, Wang J, Shao H, Shen H, Bo H, Tao C, Wu F. miR-143-3p Promotes T SCM Differentiation and Inhibits Progressive T Cell Differentiation via Inhibiting ABL2 and PAG1. Genes (Basel) 2025; 16:466. [PMID: 40282426 PMCID: PMC12027245 DOI: 10.3390/genes16040466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Adoptive cell therapy (ACT), including CAR-T and TCR-T therapies, shows promise for cancer treatment, depending on infused T cell expansion, persistence and activity. We previously characterized four T-cell subsets (TN, TSCM, TCM and TEM) and their miRNA profiles. OBJECTIVES This study investigates miR-143-3p's role in T cell differentiation. METHODS Using qPCR, we analyzed miR-143-3p expression. Target genes were validated by dual-luciferase assays. Functional assays assessed differentiation markers, proliferation, apoptosis and cytokine secretion. RESULTS miR-143-3p was upregulated in early-differentiated TSCM but downregulated during progression. We confirmed ABL2 and PAG1 as direct targets suppressed by miR-143-3p. Overexpression increased early markers (LEF1, CCR7 and CD62L) while decreasing late markers (EOMES, KLRG1 and CD45RO). It also enhanced proliferation, reduced apoptosis and suppressed cytokine secretion. CONCLUSIONS miR-143-3p promotes TSCM differentiation and inhibits progressive differentiation by targeting ABL2/PAG1, suggesting new ACT optimization strategies.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Fenglin Wu
- School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China; (W.S.); (J.H.); (H.W.); (H.Z.); (W.Z.); (J.W.); (H.S.); (H.S.); (H.B.); (C.T.)
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Li W, Zeng Y, Zhong J, Hu Y, Xiong X, Zhou Y, Fu L. Probiotics Exert Gut Immunomodulatory Effects by Regulating the Expression of Host miRNAs. Probiotics Antimicrob Proteins 2025; 17:557-568. [PMID: 39754704 DOI: 10.1007/s12602-024-10443-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 01/06/2025]
Abstract
Probiotics exert a diverse range of immunomodulatory effects on the human gut immune system. These mechanisms encompass strengthening the intestinal mucosal barrier, inhibiting pathogen adhesion and colonization, stimulating immune modulation, and fostering the production of beneficial substances. As a result, probiotics hold significant potential in the prevention and treatment of various conditions, including inflammatory bowel disease and colorectal cancer. A pivotal mechanism by which probiotics achieve these effects is through modulating the expression of host miRNAs. miRNAs, non-coding RNA molecules, are vital regulators of fundamental biological processes like cell growth, differentiation, and apoptosis. By interacting with mRNAs, miRNAs can either promote their degradation or repress their translation, thereby regulating gene expression post-transcriptionally and modulating the immune system. This review provides a comprehensive overview of how probiotics modulate gut immune responses by altering miRNA expression levels, both upregulating and downregulating specific miRNAs. It further delves into how this modulation impacts the host's resistance to pathogens and susceptibility to diseases, offering a theoretical foundation and practical insights for the clinical utilization of probiotics in disease prevention and therapy.
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Affiliation(s)
- Wenjing Li
- Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Yongwei Zeng
- Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Jiayu Zhong
- Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Youyu Hu
- Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Xia Xiong
- Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Yingshun Zhou
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China.
- Public Center of Experimental Technology of Pathogen Biology Technology Platform, Southwest Medical University, Luzhou, 646000, China.
| | - Li Fu
- Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.
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4
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Lambaren K, Trac N, Fehrenbach D, Madhur M, Chung EJ. T Cell-Targeting Nanotherapies for Atherosclerosis. Bioconjug Chem 2025; 36:332-346. [PMID: 39979082 DOI: 10.1021/acs.bioconjchem.4c00590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Cardiovascular diseases remain the leading cause of mortality worldwide. Specifically, atherosclerosis is a primary cause of acute cardiac events. However, current therapies mainly focus on lipid-lowering versus addressing the underlying inflammatory response that leads to its development and progression. Nanoparticle-mediated drug delivery offers a promising approach for targeting and regulating these inflammatory responses. In atherosclerotic lesions, inflammatory cascades result in increased T helper (Th) 1 and Th17 activity and reduced T regulatory activation. The regulation of T cell responses is critical in preventing the inflammatory imbalance in atherosclerosis, making them a key therapeutic target for nanotherapy to achieve precise atherosclerosis treatment. By functionalizing nanoparticles with targeting modalities, therapeutic agents can be delivered specifically to immune cells in atherosclerotic lesions. In this Review, we outline the role of T cells in atherosclerosis, examine current nanotherapeutic strategies for targeting T cells and modulating their differentiation, and provide perspectives for the development of nanoparticles specifically tailored to target T cells for the treatment of atherosclerosis.
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Affiliation(s)
- Karla Lambaren
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
| | - Noah Trac
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
| | - Daniel Fehrenbach
- Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Meena Madhur
- Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Eun Ji Chung
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States
- Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, United States
- Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States
- Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, United States
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, California 90089, United States
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90089, United States
- Bridge Institute, University of Southern California, Los Angeles, California 90089, United States
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Zhang RL, Wang WM, Li JQ, Li RW, Zhang J, Wu Y, Liu Y. The role of miR-155 in cardiovascular diseases: Potential diagnostic and therapeutic targets. INTERNATIONAL JOURNAL OF CARDIOLOGY. CARDIOVASCULAR RISK AND PREVENTION 2025; 24:200355. [PMID: 39760132 PMCID: PMC11699627 DOI: 10.1016/j.ijcrp.2024.200355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/21/2024] [Accepted: 12/05/2024] [Indexed: 01/07/2025]
Abstract
Cardiovascular diseases (CVDs), such as atherosclerotic cardiovascular diseases, heart failure (HF), and acute coronary syndrome, represent a significant threat to global health and impose considerable socioeconomic burdens. The intricate pathogenesis of CVD involves various regulatory mechanisms, among which microRNAs (miRNAs) have emerged as critical posttranscriptional regulators. In particular, miR-155 has demonstrated differential expression patterns across a spectrum of CVD and is implicated in the etiology and progression of arterial disorders. This systematic review synthesizes current evidence on the multifaceted roles of miR-155 in the modulation of genes and pathological processes associated with CVD. We delineate the potential of miR-155 as a diagnostic biomarker and therapeutic target, highlighting its significant regulatory influence on conditions such as atherosclerosis, aneurysm, hypertension, HF, myocardial hypertrophy, and oxidative stress. Our analysis underscores the transformative potential of miR-155 as a target for intervention in cardiovascular medicine, warranting further investigation into its clinical applicability.
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Affiliation(s)
- Rui-Lin Zhang
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Wei-Ming Wang
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital, Southwest Medical University, 646000, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases) Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
- Department of General Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Ji-Qiang Li
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Run-Wen Li
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Jie Zhang
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Ya Wu
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital, Southwest Medical University, 646000, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases) Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
- Department of General Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Yong Liu
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital, Southwest Medical University, 646000, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases) Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
- Department of General Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
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Bolha L, Hočevar A, Jurčić V. Current state of epigenetics in giant cell arteritis: Focus on microRNA dysregulation. Autoimmun Rev 2025; 24:103739. [PMID: 39732382 DOI: 10.1016/j.autrev.2024.103739] [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: 09/18/2024] [Revised: 12/23/2024] [Accepted: 12/25/2024] [Indexed: 12/30/2024]
Abstract
Giant cell arteritis (GCA) is a primary systemic vasculitis affecting the elderly, characterized by a granulomatous vessel wall inflammation of large- and medium-sized arteries. The immunopathology of GCA is complex, involving both the innate and adaptive arms of the immune system, where a maladaptive inflammatory-driven vascular repair process ultimately results in vessel wall thickening, intramural vascular smooth muscle cell proliferation, neovascularization and vessel lumen occlusion, which can lead to serious ischemic complications such as visual loss and ischemic stroke. Over the past decade, microRNA (miRNA) dysregulation has been highlighted as an important contributing factor underlying the pathogenesis of GCA. Since current understanding of miRNA involvement in GCA remains largely based on extrapolation of previously determined miRNA functions in vitro or in loss- or gain-of-function studies, an overall insight into the role of miRNA alteration in GCA pathophysiology remains limited. In this narrative review, we summarize the current knowledge on aberrantly expressed miRNAs in GCA and thoroughly discuss the impact of their altered regulatory role in the context of GCA setting. Furthermore, we address challenges and future perspectives in utilization of miRNA-based diagnostic and prognostic biomarkers of GCA in clinical settings.
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Affiliation(s)
- Luka Bolha
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
| | - Alojzija Hočevar
- Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Vesna Jurčić
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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7
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Guzmán-Martín CA, Jiménez-Ortega RF, Ortega-Springall MF, Peña-Peña M, Guerrero-Ponce AE, Vega-Memije ME, Amezcua-Guerra LM, Sánchez-Muñoz F, Springall R. miR-16-5p, miR-21-5p, and miR-155-5p in circulating vesicles as psoriasis biomarkers. Sci Rep 2025; 15:6971. [PMID: 40011539 PMCID: PMC11865590 DOI: 10.1038/s41598-025-91532-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 02/20/2025] [Indexed: 02/28/2025] Open
Abstract
Psoriasis is a chronic skin disorder marked by fast skin cell growth, leading to thick, red, scaly patches. MicroRNAs are small, non-coding RNA molecules that play a crucial role in post-transcriptional gene regulation. This study investigates miR-16-5p, miR-21-5p, and miR-155-5p expression in psoriasis EVs and assesses their biomarker potential, exploring associated target genes and pathways via bioinformatics. A cross-sectional and case-control study included 40 psoriasis patients, with blood samples collected in EDTA tubes. RNA from extracellular vesicles was isolated using Qiagen kits, and miRNAs were quantified via RT-qPCR. Bioinformatic analysis predicted target genes using databases like miRDB and TargetScan. Gene expression data from GEO was processed, and differentially expressed genes were identified. This study assessed miR-16-5p, miR-21-5p, and miR-155-5p expression in psoriasis patients' circulating vesicles versus controls, finding significantly lower levels in patients. ROC analysis confirmed their diagnostic potential. A positive correlation of miR-16-5p with the Psoriasis Area Severity Index (PASI) suggests severity marker potential. Bioinformatics identified 378 common dysregulated genes, revealing key pathways and gene interactions in psoriasis. A heat map confirmed miRNA-mediated gene suppression in the disease. This study identifies miR-16-5p, miR-21-5p, and miR-155-5p as potential psoriasis biomarkers, in addition to finding significant gene interactions and pathways involved in psoriasis pathophysiology.
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Affiliation(s)
- Carlos A Guzmán-Martín
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Mexico city, Mexico
- Departamento de Inmunología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Rogelio F Jiménez-Ortega
- Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
- Departamento de Ciencias de la Acupuntura, Universidad Estatal del Valle de Ecatepec, Ecatepec de Morelos, Mexico
| | | | - Mario Peña-Peña
- Departamento de Inmunología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | | | | | - Luis M Amezcua-Guerra
- Departamento de Inmunología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Fausto Sánchez-Muñoz
- Departamento de Inmunología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico.
| | - Rashidi Springall
- Departamento de Inmunología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico.
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8
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Tanaka A, Ishitsuka Y, Ohta H, Takenouchi N, Nakagawa M, Koh KR, Onishi C, Tanaka H, Fujimoto A, Yasunaga JI, Matsuoka M. Integrative analysis of ATAC-seq and RNA-seq for cells infected by human T-cell leukemia virus type 1. PLoS Comput Biol 2025; 21:e1012690. [PMID: 39746113 PMCID: PMC11753684 DOI: 10.1371/journal.pcbi.1012690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 01/22/2025] [Accepted: 12/02/2024] [Indexed: 01/04/2025] Open
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy (HAM) after a long latent period in a fraction of infected individuals. These HTLV-1-infected cells typically have phenotypes similar to that of CD4+T cells, but the cell status is not well understood. To extract the inherent information of HTLV-1-infected CD4+ cells, we integratively analyzed the ATAC-seq and RNA-seq data of the infected cells. Compared to CD4+T cells from healthy donors, we found anomalous chromatin accessibility in HTLV-1infected CD4+ cells derived from ATL cases in terms of location and sample-to-sample fluctuations in open chromatin regions. Further, by focusing on systematically selected genes near the open chromatin regions, we quantified the difference between the infected CD4+ cells in ATL cases and healthy CD4+T cells in terms of the correlation between the chromatin structures and the gene expressions. Based on a further analysis of chromatin accessibility, we detected TLL1 (Tolloid Like 1) as one of the key genes that exhibit unique gene expressions in ATL cases. A luciferase assay indicated that TLL1 has an isoform-dependent regulatory effect on TGF-β. Overall, this study provides results about the status of HTLV-1-infected cells, which are qualitatively consistent across the different scales of chromatin accessibility, transcription, and immunophenotype.
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Affiliation(s)
- Azusa Tanaka
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yasuhiro Ishitsuka
- Institute of Mathematics for Industry, Kyushu University, Fukuoka, Japan
| | - Hiroki Ohta
- Department of Human Sciences, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan
| | | | - Masanori Nakagawa
- Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ki-Ryang Koh
- Department of Hematology, Osaka General Hospital of West Japan Railway Company, Osaka, Japan
| | - Chiho Onishi
- Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hiromitsu Tanaka
- Department of Biophysics, Graduate school of Science, Kyoto University, Kyoto, Japan
- Department of Developmental Biology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Akihiro Fujimoto
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jun-ichirou Yasunaga
- Department of Hematology, Rheumatology and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Masao Matsuoka
- Department of Hematology, Rheumatology and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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Livshits G, Kalinkovich A. Resolution of Chronic Inflammation, Restoration of Epigenetic Disturbances and Correction of Dysbiosis as an Adjunctive Approach to the Treatment of Atopic Dermatitis. Cells 2024; 13:1899. [PMID: 39594647 PMCID: PMC11593003 DOI: 10.3390/cells13221899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/07/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with multifactorial and unclear pathogenesis. Its development is characterized by two key elements: epigenetic dysregulation of molecular pathways involved in AD pathogenesis and disrupted skin and gut microbiota (dysbiosis) that jointly trigger and maintain chronic inflammation, a core AD characteristic. Current data suggest that failed inflammation resolution is the main pathogenic mechanism underlying AD development. Inflammation resolution is provided by specialized pro-resolving mediators (SPMs) derived from dietary polyunsaturated fatty acids acting through cognate receptors. SPM levels are reduced in AD patients. Administration of SPMs or their stable, small-molecule mimetics and receptor agonists, as well as supplementation with probiotics/prebiotics, demonstrate beneficial effects in AD animal models. Epidrugs, compounds capable of restoring disrupted epigenetic mechanisms associated with the disease, improve impaired skin barrier function in AD models. Based on these findings, we propose a novel, multilevel AD treatment strategy aimed at resolving chronic inflammation by application of SPM mimetics and receptor agonists, probiotics/prebiotics, and epi-drugs. This approach can be used in conjunction with current AD therapy, resulting in AD alleviation.
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Affiliation(s)
- Gregory Livshits
- Department of Morphological Sciences, Adelson School of Medicine, Ariel University, Ariel 4077625, Israel
- Department of Anatomy and Anthropology, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel Aviv 6927846, Israel;
| | - Alexander Kalinkovich
- Department of Anatomy and Anthropology, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel Aviv 6927846, Israel;
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10
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Nouri N, Aghebati-Maleki L, Soltani-Zangbar MS, Kamrani A, Mehdizadeh A, Danaii S, Heris JA, Chakeri-Khiavi F, Yousefi M. Analysis of Th17 cell population and expression of microRNA and factors related to Th17 in patients with premature ovarian failure. J Reprod Immunol 2024; 165:104290. [PMID: 39053202 DOI: 10.1016/j.jri.2024.104290] [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: 09/27/2023] [Revised: 06/10/2024] [Accepted: 06/24/2024] [Indexed: 07/27/2024]
Abstract
Folliculogenesis is the process where follicles in the ovaries develop and eventually lead to ovulation. Any disruption to this process can cause premature ovarian failure. miR-326 is one of the microRNAs whose expression leads to Th17 production. Th17 activates the immune system to respond more vigorously, and by producing interlukins and cytokines causes inflammation and autoimmune disorders. Th17-induced inflammation and Th17/Treg imbalance can result in POF. This investigation took samples from 30 POF patients and 30 healthy people. The study utilized PCR to assess the expression levels of cytokines, specific transcription factor (ROR-γt), and miR-326. Additionally, ELISA was employed to analyze serum levels of IL-17, IL-21, IL-23. Furthermore, flow cytometry was utilized to determine the frequency of Th17. Compared to the control group, our results demonstrated a rise in the transcription factor RORɣt and a considerable rise in the frequency of Th17 cells in patients with POF. The level of inflammatory cytokines IL-17, IL-21, and IL-23 secreted in serum samples of patients with POF increased significantly compared to the control group. Results of investigating microRNA associated with Th17 cells also showed increased expression of miR-326 in females suffering from POF. The elevation of pro-inflammatory markers in women with POF contrary to the control group underscores the significant involvement of the immune system in pregnancy disorders pathogenesis. Consequently, immunological factors may serve as promising biomarkers for predicting POF likelihood in high-risk women in the future.
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Affiliation(s)
- Narjes Nouri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Sadegh Soltani-Zangbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Kamrani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center,Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahla Danaii
- Gynecology Department, Eastern Azerbaijan ACECR ART center, Eastern Azerbaijan branch of ACECR, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mehdi Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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11
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Jin S, Wan S, Xiong R, Li Y, Dong T, Guan C. The role of regulatory T cells in vitiligo and therapeutic advances: a mini-review. Inflamm Res 2024; 73:1311-1332. [PMID: 38839628 DOI: 10.1007/s00011-024-01900-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/21/2024] [Accepted: 05/29/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Regulatory T cells (Tregs) play vital roles in controlling immune reactions and maintaining immune tolerance in the body. The targeted destruction of epidermal melanocytes by activated CD8+T cells is a key event in the development of vitiligo. However, Tregs may exert immunosuppressive effects on CD8+T cells, which could be beneficial in treating vitiligo. METHODS A comprehensive search of PubMed and Web of Science was conducted to gather information on Tregs and vitiligo. RESULTS In vitiligo, there is a decrease in Treg numbers and impaired Treg functions, along with potential damage to Treg-related signaling pathways. Increasing Treg numbers and enhancing Treg function could lead to immunosuppressive effects on CD8+T cells. Recent research progress on Tregs in vitiligo has been summarized, highlighting various Treg-related therapies being investigated for clinical use. The current status of Treg-related therapeutic strategies and potential future directions for vitiligo treatment are also discussed. CONCLUSIONS A deeper understanding of Tregs will be crucial for advancing Treg-related drug discovery and treatment development in vitiligo.
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Affiliation(s)
- Shiyu Jin
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Sheng Wan
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, 310009, China
| | - Renxue Xiong
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, 310009, China
| | - Yujie Li
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Tingru Dong
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Cuiping Guan
- Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China.
- Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, 310009, China.
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12
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da Silva Duarte AJ, Sanabani SS. Deciphering epigenetic regulations in the inflammatory pathways of atopic dermatitis. Life Sci 2024; 348:122713. [PMID: 38735367 DOI: 10.1016/j.lfs.2024.122713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/29/2024] [Accepted: 05/09/2024] [Indexed: 05/14/2024]
Abstract
Atopic dermatitis, commonly referred to as atopic eczema, is a persistent inflammatory skin disorder that predominantly manifests in children but may endure into adulthood. Its clinical management poses challenges due to the absence of a definitive cure, and its prevalence varies across ethnicities, genders, and geographic locations. The epigenetic landscape of AD includes changes in DNA methylation, changes in histone acetylation and methylation, and regulation by non-coding RNAs. These changes affect inflammatory and immune mechanisms, and research has identified AD-specific variations in DNA methylation, particularly in the affected epidermis. Histone modifications, including acetylation, have been associated with the disruption of skin barrier function in AD, suggesting the potential therapeutic benefit of histone deacetylase inhibitors such as belinostat. Furthermore, non-coding RNAs, particularly microRNAs and long non-coding RNAs (lncRNAs), have been implicated in modulating various cellular processes central to AD pathogenesis. Therapeutic implications in AD include the potential use of DNA methylation inhibitors and histone deacetylase inhibitors to correct aberrant methylation patterns and modulate gene expression related to immune responses and skin barrier functions. Additionally, the emerging role of lncRNAs suggests the possibility of using small interfering RNAs or antisense oligonucleotides to inhibit lncRNAs and adjust their regulatory impact on gene expression. In conclusion, the importance of epigenetic elements in AD is becoming increasingly clear as studies highlight the contribution of DNA methylation, histone modifications and, control by non-coding RNAs to the onset and progression of the disease. Understanding these epigenetic changes provides valuable insights for developing targeted therapeutic strategies.
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Affiliation(s)
- Alberto José da Silva Duarte
- Laboratory of Medical Investigation LIM-56, Division of Dermatology, Medical School, University of São Paulo, São Paulo 05403-000, Brazil
| | - Sabri Saeed Sanabani
- Laboratory of Medical Investigation LIM-56, Division of Dermatology, Medical School, University of São Paulo, São Paulo 05403-000, Brazil; Laboratory of Medical Investigation Unit 03, Clinics Hospital, Faculty of Medicine, University of Sao Paulo, Sao Paulo 05403-000, Brazil.
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13
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Morelli M, Madonna S, Albanesi C. SOCS1 and SOCS3 as key checkpoint molecules in the immune responses associated to skin inflammation and malignant transformation. Front Immunol 2024; 15:1393799. [PMID: 38975347 PMCID: PMC11224294 DOI: 10.3389/fimmu.2024.1393799] [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: 02/29/2024] [Accepted: 06/07/2024] [Indexed: 07/09/2024] Open
Abstract
SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo.
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Affiliation(s)
| | - Stefania Madonna
- Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata - Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Rome, Italy
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14
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Tang Y, Cui G, Liu H, Han Y, Cai C, Feng Z, Shen H, Zeng S. Converting "cold" to "hot": epigenetics strategies to improve immune therapy effect by regulating tumor-associated immune suppressive cells. Cancer Commun (Lond) 2024; 44:601-636. [PMID: 38715348 PMCID: PMC11194457 DOI: 10.1002/cac2.12546] [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: 11/13/2023] [Revised: 04/09/2024] [Accepted: 04/18/2024] [Indexed: 06/26/2024] Open
Abstract
Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called "cold" tumors which are unresponsive to immunotherapy, and the opposite are "hot" tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of "cold" tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming "cold" tumors into "hot" tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy-insensitive tumors into immunotherapy-sensitive tumors which would be an innovative tendency for future immunotherapy in "cold" tumor.
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Affiliation(s)
- Yijia Tang
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Guangzu Cui
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Haicong Liu
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Ying Han
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Changjing Cai
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Ziyang Feng
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Hong Shen
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
- National Clinical Resaerch Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaHunanChina
| | - Shan Zeng
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
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15
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Perdaens O, van Pesch V. MicroRNAs are dysregulated in peripheral blood mononuclear cells in multiple sclerosis and correlate with T cell mediators. J Neuroimmunol 2024; 386:578196. [PMID: 38101084 DOI: 10.1016/j.jneuroim.2023.578196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 09/03/2023] [Accepted: 09/04/2023] [Indexed: 12/17/2023]
Abstract
T cell mediators and microRNAs are involved in the pathogenesis of multiple sclerosis (MS), but their interaction largely remains undetermined. We investigated by RT-qPCR the dysregulation of microRNAs in peripheral blood mononuclear cells of MS patients versus healthy controls, according to radiological disease activity or treatment. Several microRNAs correlated positively/negatively with IL21/FOXP3 mRNA expression, but not with serum neurofilament light chain levels. Cytokine expression is conceivably balanced by several regulators, whereas microRNAs possibly target upstream transcription factors rather than directly cytokine mRNAs. Functional studies are needed to investigate their interaction, notably for the predicted targeting of FOXP3 by miR-34c-5p.
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Affiliation(s)
- Océane Perdaens
- Neurochemistry Group, Institute of NeuroScience (IoNS), Université catholique de Louvain (UCLouvain), avenue Emmanuel Mounier 53/B1.53.03, 1200 Brussels, Belgium.
| | - Vincent van Pesch
- Neurochemistry Group, Institute of NeuroScience (IoNS), Université catholique de Louvain (UCLouvain), avenue Emmanuel Mounier 53/B1.53.03, 1200 Brussels, Belgium; Department of Neurology, Cliniques universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), avenue Hippocrate 10, 1200 Brussels, Belgium.
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16
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Rusiñol L, Puig L. Multi-Omics Approach to Improved Diagnosis and Treatment of Atopic Dermatitis and Psoriasis. Int J Mol Sci 2024; 25:1042. [PMID: 38256115 PMCID: PMC10815999 DOI: 10.3390/ijms25021042] [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: 12/16/2023] [Revised: 01/07/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
Psoriasis and atopic dermatitis fall within the category of cutaneous immune-mediated inflammatory diseases (IMIDs). The prevalence of IMIDs is increasing in industrialized societies, influenced by both environmental changes and a genetic predisposition. However, the exact immune factors driving these chronic, progressive diseases are not fully understood. By using multi-omics techniques in cutaneous IMIDs, it is expected to advance the understanding of skin biology, uncover the underlying mechanisms of skin conditions, and potentially devise precise and personalized approaches to diagnosis and treatment. We provide a narrative review of the current knowledge in genomics, epigenomics, and proteomics of atopic dermatitis and psoriasis. A literature search was performed for articles published until 30 November 2023. Although there is still much to uncover, recent evidence has already provided valuable insights, such as proteomic profiles that permit differentiating psoriasis from mycosis fungoides and β-defensin 2 correlation to PASI and its drop due to secukinumab first injection, among others.
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Affiliation(s)
- Lluís Rusiñol
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain;
- Institut de Recerca Sant Pau (IR SANT PAU), 08041 Barcelona, Spain
- Unitat Docent Hospital Universitari Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain
| | - Lluís Puig
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain;
- Institut de Recerca Sant Pau (IR SANT PAU), 08041 Barcelona, Spain
- Unitat Docent Hospital Universitari Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain
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17
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Jafarzadeh A, Chauhan P, Nemati M, Jafarzadeh S, Yoshimura A. Aberrant expression of suppressor of cytokine signaling (SOCS) molecules contributes to the development of allergic diseases. Clin Exp Allergy 2023; 53:1147-1161. [PMID: 37641429 DOI: 10.1111/cea.14385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 07/20/2023] [Accepted: 08/12/2023] [Indexed: 08/31/2023]
Abstract
Suppressor of cytokine signalling (SOCS) proteins bind to certain cytokine receptors, Janus kinases and signalling molecules to regulate signalling pathways, thus controlling immune and inflammatory responses. Dysregulated expression of various types of SOCS molecules was indicated in multiple types of allergic diseases. SOCS1, SOCS2, SOCS3, SOCS5, and cytokine-inducible SH2 domain protein (CISH) can differentially exert anti-allergic impacts through different mechanisms, such as suppressing Th2 cell development and activation, reducing eosinophilia, decreasing IgE production, repressing production of pro-allergic chemokines, promoting Treg cell differentiation and activation, suppressing Th17 cell differentiation and activation, increasing anti-allergic Th1 responses, inhibiting M2 macrophage polarization, modulating survival and development of mast cells, reducing pro-allergic activity of keratinocytes, and suppressing pulmonary fibrosis. Although some anti-allergic effects were attributed to SOCS3, it can perform pro-allergic impacts through several pathways, such as promoting Th2 cell development and activation, supporting eosinophilia, boosting pro-allergic activity of eosinophils, increasing IgE production, enhancing the expression of the pro-allergic chemokine receptor, reducing Treg cell differentiation, increasing pro-allergic Th9 responses, as well as supporting mucus secretion and collagen deposition. In this review, we discuss the contrasting roles of SOCS proteins in contexts of allergic disorders to provide new insights regarding the pathophysiology of these diseases and possibly explore SOCS proteins as potential therapeutic targets for alleviating allergies.
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Affiliation(s)
- Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Prashant Chauhan
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice, Czech Republic
- Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic
| | - Maryam Nemati
- Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Sara Jafarzadeh
- Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
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18
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Pandey R, Bakay M, Hakonarson H. SOCS-JAK-STAT inhibitors and SOCS mimetics as treatment options for autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis. Front Immunol 2023; 14:1271102. [PMID: 38022642 PMCID: PMC10643230 DOI: 10.3389/fimmu.2023.1271102] [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: 08/01/2023] [Accepted: 10/02/2023] [Indexed: 12/01/2023] Open
Abstract
Autoimmune diseases arise from atypical immune responses that attack self-tissue epitopes, and their development is intricately connected to the disruption of the JAK-STAT signaling pathway, where SOCS proteins play crucial roles. Conditions such as autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis exhibit immune system dysfunctions associated with JAK-STAT signaling dysregulation. Emerging therapeutic strategies utilize JAK-STAT inhibitors and SOCS mimetics to modulate immune responses and alleviate autoimmune manifestations. Although more research and clinical studies are required to assess their effectiveness, safety profiles, and potential for personalized therapeutic approaches in autoimmune conditions, JAK-STAT inhibitors and SOCS mimetics show promise as potential treatment options. This review explores the action, effectiveness, safety profiles, and future prospects of JAK inhibitors and SOCS mimetics as therapeutic agents for psoriasis, autoimmune uveitis, systemic lupus erythematosus, and autoimmune encephalitis. The findings underscore the importance of investigating these targeted therapies to advance treatment options for individuals suffering from autoimmune diseases.
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Affiliation(s)
- Rahul Pandey
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Marina Bakay
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Hakon Hakonarson
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, PA, United States
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19
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Jiang X, Shi R, Ma R, Tang X, Gong Y, Yu Z, Shi Y. The role of microRNA in psoriasis: A review. Exp Dermatol 2023; 32:1598-1612. [PMID: 37382420 DOI: 10.1111/exd.14871] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 06/30/2023]
Abstract
Psoriasis is a chronic immune-mediated inflammatory skin disease that involves a complex interplay between infiltrated immune cells and keratinocytes. Great progress has been made in the research on the molecular mechanism of coding and non-coding genes, which has helped in clinical treatment. However, our understanding of this complex disease is far from clear. MicroRNAs (miRNAs) are small non-coding RNA molecules that are involved in post-transcriptional regulation, characterised by their role in mediating gene silencing. Recent studies on miRNAs have revealed their important role in the pathogenesis of psoriasis. We reviewed the current advances in the study of miRNAs in psoriasis; the existing research has found that dysregulated miRNAs in psoriasis notably affect keratinocyte proliferation and/or differentiation processes, as well as inflammation progress. In addition, miRNAs also influence the function of immune cells in psoriasis, including CD4+ T cells, dendritic cells, Langerhans cells and so on. In addition, we discuss possible miRNA-based therapy for psoriasis, such as the topical delivery of exogenous miRNAs, miRNA antagonists and miRNA mimics. Our review highlights the potential role of miRNAs in the pathogenesis of psoriasis, and we expect more research progress with miRNAs in the future, which will help us understand this complex skin disease more accurately.
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Affiliation(s)
- Xingyu Jiang
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Rongcan Shi
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Rui Ma
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Xinyi Tang
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Yu Gong
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Zengyang Yu
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Yuling Shi
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
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20
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Aslanian-Kalkhoran L, Kamrani A, Alipourfard I, Chakari-Khiavi F, Chakari-Khiavi A, Aghebati-Maleki L, Shekarchi AA, Mehdizadeh A, Mojahedi M, Danaii S, Roshangar L, Ahmadian Heris J, Zolfaghari M, Dolati S, Soltani-Zangbar MS, Yousefi M. The effect of lymphocyte immunotherapy (LIT) in modulating immune responses in patients with recurrent pregnancy loss (RPL). Int Immunopharmacol 2023; 121:110326. [PMID: 37290322 DOI: 10.1016/j.intimp.2023.110326] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 06/10/2023]
Abstract
In order to prevent miscarriage in RPL patients, the goal of this study was to determine how well lymphocyte immunotherapy (LIT) works in modifying immunological responses produced by cells, cytokines, transcription factors, and microRNAs. 200 RPL patients and 200 healthy controls were included in the study. Using flow cytometry, it was possible to compare the frequency of cells before and after lymphocyte treatment. Real-time PCR was used to assess the gene expression levels of transcription factors, cytokines, and microRNAs. ELISA method was used to evaluate the level of secretion of cytokines in the serum. Primary evaluation of the immune profile between healthy controls and RPL cases showed a higher frequency of Th17, NK, B cells and a lower frequency of Treg cells in RPL cases. Also, pro-inflammatory cytokines showed increased expression at mRNA and protein levels in the RPL group in comparison with the control group. Whereas, anti-inflammatory cytokines showed decreased expression in RPL patients. Decreased and increased frequency of Th17 and Treg lymphocytes observed in RPL cases following LIT, respectively. The same results obtained for RORγt and FoxP3 mRNA expression as transcription factor of Th17 and Treg cells, respectively. NK cell cytotoxicity decreased after LIT in RPL patients. miR-326a and miR-155 expression after LIT reduced, but miR-146a and miR-10a expression increased in RPL instances. LIT in RPL cases causes to elevation and modulation of anti-inflammatory and pro-inflammatory cytokines. Our data showed that lymphocyte therapy can be proposed as an effective therapeutic agent in RPL patients with immunological background by a modulating inflammatory condition.
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Affiliation(s)
- Lida Aslanian-Kalkhoran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Kamrani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Iraj Alipourfard
- Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland
| | - Forough Chakari-Khiavi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aref Chakari-Khiavi
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Ali Akbar Shekarchi
- Department of Pathology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Mojahedi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahla Danaii
- Gynecology Department, Eastern Azerbaijan ACECR ART center, Eastern Azerbaijan branch of ACECR, Tabriz, Iran
| | - Leila Roshangar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammadali Zolfaghari
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanam Dolati
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Sadegh Soltani-Zangbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mehdi Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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21
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Golzari-Sorkheh M, Zúñiga-Pflücker JC. Development and function of FOXP3+ regulators of immune responses. Clin Exp Immunol 2023; 213:13-22. [PMID: 37085947 PMCID: PMC10324550 DOI: 10.1093/cei/uxad048] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/08/2023] [Accepted: 04/21/2023] [Indexed: 04/23/2023] Open
Abstract
The Forkhead Box P3 (FOXP3) protein is an essential transcription factor for the development and function of regulatory T cells (Tregs), involved in the maintenance of immunological tolerance. Although extensive research over the last decade has investigated the critical role of FOXP3+ cells in preserving immune homeostasis, our understanding of their specific functions remains limited. Therefore, unveiling the molecular mechanisms underpinning the up- and downstream transcriptional regulation of and by FOXP3 is crucial for developing Treg-targeted therapeutics. Dysfunctions in FOXP3+ Tregs have also been found to be inherent drivers of autoimmune disorders and have been shown to exhibit multifaceted functions in the context of cancer. Recent research suggests that these cells may also be involved in tissue-specific repair and regeneration. Herein, we summarize current understanding of the thymic-transcriptional regulatory landscape of FOXP3+ Tregs, their epigenetic modulators, and associated signaling pathways. Finally, we highlight the contributions of FOXP3 on the functional development of Tregs and reflect on the clinical implications in the context of pathological and physiological immune responses.
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Affiliation(s)
| | - Juan Carlos Zúñiga-Pflücker
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada
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22
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Palideh A, Vaghari-Tabari M, Nosrati Andevari A, Qujeq D, Asemi Z, Alemi F, Rouhani Otaghsara H, Rafieyan S, Yousefi B. MicroRNAs and Periodontal Disease: Helpful Therapeutic Targets? Adv Pharm Bull 2023; 13:423-434. [PMID: 37646047 PMCID: PMC10460817 DOI: 10.34172/apb.2023.048] [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: 08/23/2021] [Revised: 05/07/2022] [Accepted: 07/01/2022] [Indexed: 09/01/2023] Open
Abstract
Periodontal disease is the most common oral disease. This disease can be considered as an inflammatory disease. The immune response to bacteria accumulated in the gum line plays a key role in the pathogenesis of periodontal disease. In addition to immune cells, periodontal ligament cells and gingival epithelial cells are also involved in the pathogenesis of this disease. miRNAs which are small RNA molecules with around 22 nucleotides have a considerable relationship with the immune system affecting a wide range of immunological events. These small molecules are also in relation with periodontium tissues especially periodontal ligament cells. Extensive studies have been performed in recent years on the role of miRNAs in the pathogenesis of periodontal disease. In this review paper, we have reviewed the results of these studies and discussed the role of miRNAs in the immunopathogenesis of periodontal disease comprehensively. miRNAs play an important role in the pathogenesis of periodontal disease and maybe helpful therapeutic targets for the treatment of periodontal disease.
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Affiliation(s)
| | - Mostafa Vaghari-Tabari
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Nosrati Andevari
- Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Department of Clinical Biochemistry, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Forough Alemi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Sona Rafieyan
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Bratu D, Boda D, Caruntu C. Genomic, Epigenomic, Transcriptomic, Proteomic and Metabolomic Approaches in Atopic Dermatitis. Curr Issues Mol Biol 2023; 45:5215-5231. [PMID: 37367080 PMCID: PMC10297041 DOI: 10.3390/cimb45060331] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/03/2023] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with a high prevalence in the developed countries. It is associated with atopic and non-atopic diseases, and its close correlation with atopic comorbidities has been genetically demonstrated. One of the main roles of genetic studies is to comprehend the defects of the cutaneous barrier due to filaggrin deficit and epidermal spongiosis. Recently, epigenetic studies started to analyze the influence of the environmental factors on gene expression. The epigenome is considered to be a superior second code that controls the genome, which includes alterations of the chromatin. The epigenetic changes do not alter the genetic code, however, changes in the chromatin structure could activate or inhibit the transcription process of certain genes and consequently, the translation process of the new mRNA into a polypeptide chain. In-depth analysis of the transcriptomic, metabolomic and proteomic studies allow to unravel detailed mechanisms that cause AD. The extracellular space and lipid metabolism are associated with AD that is independent of the filaggrin expression. On the other hand, around 45 proteins are considered as the principal components in the atopic skin. Moreover, genetic studies based on the disrupted cutaneous barrier can lead to the development of new treatments targeting the cutaneous barrier or cutaneous inflammation. Unfortunately, at present, there are no target therapies that focus on the epigenetic process of AD. However, in the future, miR-143 could be an important objective for new therapies, as it targets the miR-335:SOX axis, thereby restoring the miR-335 expression, and repairing the cutaneous barrier defects.
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Affiliation(s)
- Dalia Bratu
- Department of Dermatology, ‘Colentina’ Clinical Hospital, 020125 Bucharest, Romania;
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Daniel Boda
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Dermatology, ‘Ponderas’ Academic Hospital, 014142 Bucharest, Romania
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | - Constantin Caruntu
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
- Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Zapata-Martínez L, Águila S, de los Reyes-García AM, Carrillo-Tornel S, Lozano ML, González-Conejero R, Martínez C. Inflammatory microRNAs in cardiovascular pathology: another brick in the wall. Front Immunol 2023; 14:1196104. [PMID: 37275892 PMCID: PMC10233054 DOI: 10.3389/fimmu.2023.1196104] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 05/08/2023] [Indexed: 06/07/2023] Open
Abstract
The regulatory role of microRNAs (miRNAs) is mainly mediated by their effect on protein expression and is recognized in a multitude of pathophysiological processes. In recent decades, accumulating evidence has interest in these factors as modulatory elements of cardiovascular pathophysiology. Furthermore, additional biological processes have been identified as new components of cardiovascular disease etiology. In particular, inflammation is now considered an important cardiovascular risk factor. Thus, in the present review, we will focus on the role of a subset of miRNAs called inflamma-miRs that may regulate inflammatory status in the development of cardiovascular pathology. According to published data, the most representative candidates that play functional roles in thromboinflammation are miR-21, miR-33, miR-34a, miR-146a, miR-155, and miR-223. We will describe the functions of these miRNAs in several cardiovascular pathologies in depth, with specific emphasis on the molecular mechanisms related to atherogenesis. We will also discuss the latest findings on the role of miRNAs as regulators of neutrophil extracellular traps and their impact on cardiovascular diseases. Overall, the data suggest that the use of miRNAs as therapeutic tools or biomarkers may improve the diagnosis or prognosis of adverse cardiovascular events in inflammatory diseases. Thus, targeting or increasing the levels of adequate inflamma-miRs at different stages of disease could help mitigate or avoid the development of cardiovascular morbidities.
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25
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Yan YN, Zhang J, Yang N, Chen C, Li W. T Cell Subsets and the Expression of Related MicroRNAs in Patients with Recurrent Early Pregnancy Loss. Mediators Inflamm 2023; 2023:8215567. [PMID: 37035756 PMCID: PMC10076117 DOI: 10.1155/2023/8215567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/30/2022] [Accepted: 10/05/2022] [Indexed: 03/31/2023] Open
Abstract
This study explored the role of T cell subsets and the expression of related microRNAs in patients with recurrent early pregnancy loss (EPL). Fifty patients with EPL loss between May 2018 and May 2021 were randomly selected as the EPL group, and 50 pregnant women with normal pregnancies or normal delivery outcomes were randomly selected as the control group. The expression levels of T cell subset-related markers and T cell subset-related miRNAs, in addition to the frequencies of T cell subsets, in peripheral blood of the two groups were analyzed. In terms of T cell-related markers, the results showed that the expression levels of the transcriptional regulator TBX-21 (T-bet) and interferon regulatory factor 4 (IRF4) were significantly upregulated in peripheral blood of the patients in the EPL group (
), whereas the expression levels of GATA binding protein 3 (GATA3) and glucocorticoid-induced tumor necrosis factor receptor (GITR) were significantly downregulated (
). In the EPL group, the expression of mir-106b, mir-93, and mir-25 was upregulated (
,
, and
, respectively) in regulatory T (Treg) cell-related T cell subsets, whereas the expression of miR-146a and miR-155 was downregulated (
). The frequencies of Treg and exhausted T cells in the EPL group were significantly lower than those in the control group (
). The cell frequencies of T helper 17 (Th17) cells and exhausted Treg cells in the EPL group were significantly higher than those in the control group (
). In conclusion, immune cells and associated miRNA profiles can be used as prognostic biomarkers for the treatment of human reproductive disorders, such as EPL.
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Ibáñez-Cabellos JS, Pallardó FV, García-Giménez JL, Seco-Cervera M. Oxidative Stress and Epigenetics: miRNA Involvement in Rare Autoimmune Diseases. Antioxidants (Basel) 2023; 12:antiox12040800. [PMID: 37107175 PMCID: PMC10135388 DOI: 10.3390/antiox12040800] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/16/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
Autoimmune diseases (ADs) such as Sjögren’s syndrome, Kawasaki disease, and systemic sclerosis are characterized by chronic inflammation, oxidative stress, and autoantibodies, which cause joint tissue damage, vascular injury, fibrosis, and debilitation. Epigenetics participate in immune cell proliferation and differentiation, which regulates the development and function of the immune system, and ultimately interacts with other tissues. Indeed, overlapping of certain clinical features between ADs indicate that numerous immunologic-related mechanisms may directly participate in the onset and progression of these diseases. Despite the increasing number of studies that have attempted to elucidate the relationship between miRNAs and oxidative stress, autoimmune disorders and oxidative stress, and inflammation and miRNAs, an overall picture of the complex regulation of these three actors in the pathogenesis of ADs has yet to be formed. This review aims to shed light from a critical perspective on the key AD-related mechanisms by explaining the intricate regulatory ROS/miRNA/inflammation axis and the phenotypic features of these rare autoimmune diseases. The inflamma-miRs miR-155 and miR-146, and the redox-sensitive miR miR-223 have relevant roles in the inflammatory response and antioxidant system regulation of these diseases. ADs are characterized by clinical heterogeneity, which impedes early diagnosis and effective personalized treatment. Redox-sensitive miRNAs and inflamma-miRs can help improve personalized medicine in these complex and heterogeneous diseases.
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Affiliation(s)
| | - Federico V. Pallardó
- U733, Centre for Biomedical Network Research on Rare Diseases (CIBERER-ISCIII), 28029 Madrid, Spain
- Mixed Unit for Rare Diseases INCLIVA-CIPF, INCLIVA Health Research Institute, 46010 Valencia, Spain
- Department Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
- Correspondence: (F.V.P.); (J.L.G.-G.); (M.S.-C.); Tel.: +34-963-864-646 (F.V.P.)
| | - José Luis García-Giménez
- U733, Centre for Biomedical Network Research on Rare Diseases (CIBERER-ISCIII), 28029 Madrid, Spain
- Mixed Unit for Rare Diseases INCLIVA-CIPF, INCLIVA Health Research Institute, 46010 Valencia, Spain
- Department Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
- Correspondence: (F.V.P.); (J.L.G.-G.); (M.S.-C.); Tel.: +34-963-864-646 (F.V.P.)
| | - Marta Seco-Cervera
- Hospital Dr. Peset, Fundación para la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, FISABIO, 46010 Valencia, Spain
- Correspondence: (F.V.P.); (J.L.G.-G.); (M.S.-C.); Tel.: +34-963-864-646 (F.V.P.)
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27
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Aloi MS, Prater KE, Sánchez REA, Beck A, Pathan JL, Davidson S, Wilson A, Keene CD, de la Iglesia H, Jayadev S, Garden GA. Microglia specific deletion of miR-155 in Alzheimer's disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures. J Neuroinflammation 2023; 20:60. [PMID: 36879321 PMCID: PMC9990295 DOI: 10.1186/s12974-023-02745-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 02/21/2023] [Indexed: 03/08/2023] Open
Abstract
Alzheimer's Disease (AD) is characterized by the accumulation of extracellular amyloid-β (Aβ) as well as CNS and systemic inflammation. Microglia, the myeloid cells resident in the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNAs (miRNAs) modulate inflammatory responses in microglia, and miRNA profiles are altered in Alzheimer's disease (AD) patients. Expression of the pro-inflammatory miRNA, miR-155, is increased in the AD brain. However, the role of miR-155 in AD pathogenesis is not well-understood. We hypothesized that miR-155 participates in AD pathophysiology by regulating microglia internalization and degradation of Aβ. We used CX3CR1CreER/+ to drive-inducible, microglia-specific deletion of floxed miR-155 alleles in two AD mouse models. Microglia-specific inducible deletion of miR-155 in microglia increased anti-inflammatory gene expression while reducing insoluble Aβ1-42 and plaque area. Yet, microglia-specific miR-155 deletion led to early-onset hyperexcitability, recurring spontaneous seizures, and seizure-related mortality. The mechanism behind hyperexcitability involved microglia-mediated synaptic pruning as miR-155 deletion altered microglia internalization of synaptic material. These data identify miR-155 as a novel modulator of microglia Aβ internalization and synaptic pruning, influencing synaptic homeostasis in the setting of AD pathology.
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Affiliation(s)
- Macarena S Aloi
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington, Seattle, WA, 98195, USA
- Department of Neurology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Katherine E Prater
- Department of Neurology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | | | - Asad Beck
- Department of Biology, University of Washington, Seattle, WA, 98109, USA
| | - Jasmine L Pathan
- Department of Neurology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Stephanie Davidson
- Department of Neurology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Angela Wilson
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington, Seattle, WA, 98195, USA
| | - C Dirk Keene
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Washington, Seattle, WA, 98195, USA
| | | | - Suman Jayadev
- Department of Neurology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Gwenn A Garden
- Department of Neurology, University of Washington School of Medicine, Seattle, WA, 98195, USA.
- Department of Neurology, University of North Carolina at Chapel Hill, 170 Manning Drive, Chapel Hill, NC, 27517, USA.
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28
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Martínez-Hernández R, Marazuela M. MicroRNAs in autoimmune thyroid diseases and their role as biomarkers. Best Pract Res Clin Endocrinol Metab 2023; 37:101741. [PMID: 36801129 DOI: 10.1016/j.beem.2023.101741] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level. They are emerging as potential biomarkers and as therapeutic targets for several diseases including autoimmune thyroid diseases (AITD). They control a wide range of biological phenomena, including immune activation, apoptosis, differentiation and development, proliferation and metabolism. This function makes miRNAs attractive as disease biomarker candidates or even as therapeutic agents. Because of their stability and reproducibility circulating miRNAs have been an interesting area of research in many diseases, and studies describing their role in the immune response and in autoimmune diseases have progressively developed. The mechanisms underlying AITD remain elusive. AITD pathogenesis is characterized by a multifactorial interplay based on the synergy between susceptibility genes and environmental stimulation, together with epigenetic modulation. Understanding the regulatory role of miRNAs could lead to identify potential susceptibility pathways, diagnostic biomarkers and therapeutic targets for this disease. Herein we update our present knowledge on the role of microRNAs in AITD and discuss on their importance as possible diagnostic and prognostic biomarkers in the most prevalent AITDs: Hashimoto's thyroiditis (HT), Graves' disease (GD) and Graves' Ophthalmopathy (GO). This review provides an overview of the state of the art in the pathological roles of microRNAs as well as in possible novel miRNA-based therapeutic approaches in AITD.
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Affiliation(s)
- Rebeca Martínez-Hernández
- Department of Endocrinology, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, C/ Diego de León 62, 28006 Madrid, Spain; Faculty of Medicine, Universidad San Pablo CEU, CEU Universities, Urbanizacion Monteprincipe, Alcorcon, Madrid, Spain.
| | - Mónica Marazuela
- Department of Endocrinology, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, C/ Diego de León 62, 28006 Madrid, Spain.
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29
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Jahangir M, Kahrizi MS, Natami M, Moaref Pour R, Ghoreishizadeh S, Hemmatzadeh M, Mohammadi H, Shomali N, Sandoghchian Shotorbani S. MicroRNA-155 acts as a potential prognostic and diagnostic factor in patients with ankylosing spondylitis by modulating SOCS3. Mol Biol Rep 2023; 50:553-563. [PMID: 36350418 DOI: 10.1007/s11033-022-08033-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 10/14/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Ankylosing spondylitis (AS) is a progressive inflammatory disease. Our primary objective was to explore the role of miR-155 and its targeted factors in AS pathogenesis. METHODS AND RESULTS PBMCs were isolated from 30 AS patients and 30 healthy individuals using the Ficoll-hypaque isolation approach. The expression of miR-155 and its associated targets, including Suppressor Of Cytokine Signaling 3 (SOCS3), STAT3, and IL-21, were determined using qT-qPCR. Then, PBMCs were cultured, and the effect of miR-155, SOCS3 siRNA (to suppress its expression), pEFSOCS3 (enforced expression), and their combination were investigated by qRT-PCR and western blotting. We also treated the cultured PBMCs with Brefeldin A, a potent inhibitor of cytokine secretion, to determine its effect on IL-21 expression and secretion. In addition, the association between miR-155 and patients' clinicopathological features was examined. The results showed that miR-155, IL-21, and STAT3 were increased in patients with AS, while SOCS3 had decreasing expression trend. It was also determined that miR-155 alleviates SOCS3 expression and increases IL-21 and STAT3 expression; it had a prominent effect when combined with SOCS3 siRNA. Besides, we showed that simultaneous transfection of miR-155 and pEFSOCS3 had no significant effect on IL-21 and STAT3 expression, revealing that miR-155 could alleviate the enforced expression of SOCS3. It was also proven that Brefledine A led to IL-21 up-regulation or accumulation while relieving its secretion. Also, a significant correlation between miR-155 and pathological features of AS patients was found. CONCLUSION miR-155 acts as a potential prognostic and diagnostic biomarker. Its up-regulation leads to the down-regulation of SOCS3 and increased expression of IL-21 and STAT3 as characteristic of TH-17 lymphocytes, leading to worsening inflammatory conditions in patients with AS.
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Affiliation(s)
| | | | - Mohammad Natami
- Department of Urology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Raziyeh Moaref Pour
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Maryam Hemmatzadeh
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
- Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Siamak Sandoghchian Shotorbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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30
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Wen J, Wu Y, Tian Y, Han J, Wang Q, Liu Y, Man C. Circulating miR-155, a potential regulator of immune responses to different vaccines in chicken. Res Vet Sci 2022; 152:670-677. [DOI: 10.1016/j.rvsc.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 07/01/2022] [Accepted: 10/03/2022] [Indexed: 11/19/2022]
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Kovoor E, Chauhan SK, Hajrasouliha A. Role of inflammatory cells in pathophysiology and management of diabetic retinopathy. Surv Ophthalmol 2022; 67:1563-1573. [PMID: 35914582 PMCID: PMC11082823 DOI: 10.1016/j.survophthal.2022.07.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 07/18/2022] [Accepted: 07/25/2022] [Indexed: 02/05/2023]
Abstract
Diabetic retinopathy (DR) is a sight-threatening complication of diabetes mellitus. Several inflammatory cells and proteins, including macrophages and microglia, cytokines, and vascular endothelial growth factors, are found to play a significant role in the development and progression of DR. Inflammatory cells play a significant role in the earliest changes seen in DR including the breakdown of the blood retinal barrier leading to leakage of blood into the retina. They also have an important role in the pathogenesis of more advanced stage of proliferative diabetic retinopathy, leading to neovascularization, vitreous hemorrhage, and tractional retinal detachment. In this review, we examine the function of numerous inflammatory cells involved in the pathogenesis, progression, and role as a potential therapeutic target in DR. Additionally, we explore the role of inflammation following treatment of DR.
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Affiliation(s)
- Elias Kovoor
- Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Sunil K Chauhan
- Schepens Eye Institute, Harvard Medical School, Boston, MA, USA
| | - Amir Hajrasouliha
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
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Dhuppar S, Murugaiyan G. miRNA effects on gut homeostasis: therapeutic implications for inflammatory bowel disease. Trends Immunol 2022; 43:917-931. [PMID: 36220689 PMCID: PMC9617792 DOI: 10.1016/j.it.2022.09.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 09/05/2022] [Accepted: 09/11/2022] [Indexed: 01/12/2023]
Abstract
Inflammatory bowel disease (IBD) spans a range of chronic conditions affecting the gastrointestinal (GI) tract, which are marked by intermittent flare-ups and remissions. IBD results from microbial dysbiosis or a defective mucosal barrier in the gut that triggers an inappropriate immune response in a genetically susceptible person, altering the immune-microbiome axis. In this review, we discuss the regulatory roles of miRNAs, small noncoding RNAs with gene regulatory functions, in the stability and maintenance of the gut immune-microbiome axis, and detail the challenges and recent advances in the use of miRNAs as putative therapeutic agents for treating IBD.
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Affiliation(s)
- Shivnarayan Dhuppar
- Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Current address: Centre for Business Innovation, The Indian School of Business, Hyderabad 500111, India
| | - Gopal Murugaiyan
- Ann Romney Center for Neurological Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Role of miR-155 in inflammatory autoimmune diseases: a comprehensive review. Inflamm Res 2022; 71:1501-1517. [DOI: 10.1007/s00011-022-01643-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 09/09/2022] [Accepted: 09/10/2022] [Indexed: 11/05/2022] Open
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Tang F, Zhou Z, Huang K, Deng W, Lin J, Chen R, Li M, Xu F. MicroRNAs in the regulation of Th17/Treg homeostasis and their potential role in uveitis. Front Genet 2022; 13:848985. [PMID: 36186459 PMCID: PMC9515448 DOI: 10.3389/fgene.2022.848985] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 08/24/2022] [Indexed: 11/25/2022] Open
Abstract
Th17 and regulatory T cells (Tregs) play crucial roles in the pathogenesis of autoimmune diseases. Th17/Treg homeostasis is critically involved in maintaining the immune balance. Disturbed Th17/Treg homeostasis contributes to the progression of autoimmune diseases. MicroRNAs (miRNAs) have emerged as a new vital factor in the regulation of disturbed Th17/Treg homeostasis. To better understand the epigenetic mechanisms of miRNAs in regulating Treg/Th17 homeostasis, we included and evaluated 97 articles about autoimmune diseases and found that miRNAs were involved in the regulation of Treg/Th17 homeostasis from several aspects positively or negatively, including Treg differentiation and development, Treg induction, Treg stability, Th17 differentiation, and Treg function. Uveitis is one of the ocular autoimmune diseases, which is also characterized with Th17/Treg imbalance. However, our understanding of the miRNAs in the pathogenesis of uveitis is elusive and not well-studied. In this review, we further summarized miRNAs found to be involved in autoimmune uveitis and their potential role in the regulation of Th17/Treg homeostasis.
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Affiliation(s)
| | | | | | | | | | | | - Min Li
- *Correspondence: Fan Xu, ; Min Li,
| | - Fan Xu
- *Correspondence: Fan Xu, ; Min Li,
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35
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Zhao C, Li XY, Li ZY, Li M, Liu ZD. Moxibustion regulates T-regulatory/T-helper 17 cell balance by modulating the microRNA-221/suppressor of cytokine signaling 3 axis in a mouse model of rheumatoid arthritis. JOURNAL OF INTEGRATIVE MEDICINE 2022; 20:453-462. [PMID: 35729047 DOI: 10.1016/j.joim.2022.06.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 05/30/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE Rheumatoid arthritis (RA) progression is associated with the balance of T-regulatory (Treg) and T-helper 17 (Th17) cells, while the role of microRNAs (miRs) in regulating Treg/Th17 cell balance has not been clarified. This study aimed to assess whether moxibustion could regulate Treg/Th17 cell balance by modulating the miR-221/suppressor of cytokine signaling 3 (SOCS3) axis in the RA mouse model. METHODS A mouse model of collagen-induced arthritis (CIA) was established in male DBA/1J mice. Twenty-two days after CIA induction, the mice received daily treatment with moxibustion for 12 times. Pathological scores were assessed according to the levels of synovial hyperplasia. The expression levels of cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-17 and IL-10 were analyzed in serum by enzyme-linked immunosorbent assay. The cluster of differentiation 4 (CD4+) splenocytes was analyzed by fluorescence-activated cell sorting. The expression levels of RA-related miRs and target genes were subsequently detected, and the target of miR-221 was confirmed by the dual-luciferase reporter assay. RESULTS It was revealed that moxibustion treatment decreased the pathological scores and downregulated the expression levels of IL-1β, IL-6, TNF-α, IFN-γ and IL-17, while upregulated the expression level of IL-10. The Treg/Th17 cell balance was regulated by moxibustion treatment. The expression level of miR-221 was suppressed by moxibustion treatment. Furthermore, SOCS3 was found as the direct target of miR-221, which mediated the function of moxibustion by regulating the Treg/Th17 cell balance. CONCLUSION Moxibustion therapy regulated the Treg/Th17 cell balance by modulating the miR-221/SOCS3 axis in the RA mouse model.
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Affiliation(s)
- Chuang Zhao
- Department of Acupuncture, Baoshan Branch of Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201999, China; Department of Acupuncture, Baoshan Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai 201999, China
| | - Xiao-Yan Li
- Department of Acupuncture, Baoshan Branch of Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201999, China; Department of Acupuncture, Baoshan Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai 201999, China
| | - Zun-Yuan Li
- Department of Acupuncture, Baoshan Branch of Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201999, China; Department of Acupuncture, Baoshan Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai 201999, China
| | - Miao Li
- Department of Acupuncture, Baoshan Branch of Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201999, China; Department of Acupuncture, Baoshan Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai 201999, China
| | - Zhi-Dan Liu
- Department of Acupuncture, Baoshan Branch of Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201999, China; Department of Acupuncture, Baoshan Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai 201999, China.
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Zhu JJ, Stenfeldt C, Bishop EA, Canter JA, Eschbaumer M, Rodriguez LL, Arzt J. Inferred Causal Mechanisms of Persistent FMDV Infection in Cattle from Differential Gene Expression in the Nasopharyngeal Mucosa. Pathogens 2022; 11:pathogens11080822. [PMID: 35894045 PMCID: PMC9329776 DOI: 10.3390/pathogens11080822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/14/2022] [Accepted: 07/18/2022] [Indexed: 02/05/2023] Open
Abstract
Foot-and-mouth disease virus (FMDV) can persistently infect pharyngeal epithelia in ruminants but not in pigs. Our previous studies demonstrated that persistent FMDV infection in cattle was associated with under-expression of several chemokines that recruit immune cells. This report focuses on the analysis of differentially expressed genes (DEG) identified during the transitional phase of infection, defined as the period when animals diverge between becoming carriers or terminators. During this phase, Th17-stimulating cytokines (IL6 and IL23A) and Th17-recruiting chemokines (CCL14 and CCL20) were upregulated in animals that were still infected (transitional carriers) compared to those that had recently cleared infection (terminators), whereas chemokines recruiting neutrophils and CD8+ T effector cells (CCL3 and ELR+CXCLs) were downregulated. Upregulated Th17-specific receptor, CCR6, and Th17-associated genes, CD146, MIR155, and ThPOK, suggested increased Th17 cell activity in transitional carriers. However, a complex interplay of the Th17 regulatory axis was indicated by non-significant upregulation of IL17A and downregulation of IL17F, two hallmarks of TH17 activity. Other DEG suggested that transitional carriers had upregulated aryl hydrocarbon receptor (AHR), non-canonical NFκB signaling, and downregulated canonical NFκB signaling. The results described herein provide novel insights into the mechanisms of establishment of FMDV persistence. Additionally, the fact that ruminants, unlike pigs, produce a large amount of AHR ligands suggests a plausible explanation of why FMDV persists in ruminants, but not in pigs.
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Affiliation(s)
- James J. Zhu
- Foreign Animal Disease Research Unit, Plum Island Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Orient, NY 11957, USA; (C.S.); (E.A.B.); (J.A.C.); (L.L.R.)
- Correspondence: (J.J.Z.); (J.A.); Tel.: +1-631-323-3340 (J.J.Z.); +1-631-323-4421 (J.A.); Fax: +1-631-323-3006 (J.A.)
| | - Carolina Stenfeldt
- Foreign Animal Disease Research Unit, Plum Island Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Orient, NY 11957, USA; (C.S.); (E.A.B.); (J.A.C.); (L.L.R.)
- Department of Diagnostic Medicine/Pathobiology, Kansas State University, Manhattan, KS 66506, USA
| | - Elizabeth A. Bishop
- Foreign Animal Disease Research Unit, Plum Island Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Orient, NY 11957, USA; (C.S.); (E.A.B.); (J.A.C.); (L.L.R.)
| | - Jessica A. Canter
- Foreign Animal Disease Research Unit, Plum Island Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Orient, NY 11957, USA; (C.S.); (E.A.B.); (J.A.C.); (L.L.R.)
- Plum Island Animal Disease Center Research Participation Program, Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN 37830, USA
| | - Michael Eschbaumer
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany;
| | - Luis L. Rodriguez
- Foreign Animal Disease Research Unit, Plum Island Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Orient, NY 11957, USA; (C.S.); (E.A.B.); (J.A.C.); (L.L.R.)
| | - Jonathan Arzt
- Foreign Animal Disease Research Unit, Plum Island Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Orient, NY 11957, USA; (C.S.); (E.A.B.); (J.A.C.); (L.L.R.)
- Correspondence: (J.J.Z.); (J.A.); Tel.: +1-631-323-3340 (J.J.Z.); +1-631-323-4421 (J.A.); Fax: +1-631-323-3006 (J.A.)
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Cheng J, Zhang Y, Yang J, Wang Y, Xu J, Fan Y. MiR-155-5p modulates inflammatory phenotype of activated oral lichen-planus-associated-fibroblasts by targeting SOCS1. Mol Biol Rep 2022; 49:7783-7792. [PMID: 35733067 DOI: 10.1007/s11033-022-07603-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 05/12/2022] [Accepted: 05/13/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disease. Cytokines are closely associated with OLP development. In addition to immune cells, fibroblasts have been reported to induce regional inflammation. MicroRNA(miR)-155-5p is reportedly increased significantly in OLP and is known to regulate inflammation. This study aimed to investigate the role of miR-155-5p in fibroblasts of OLP lesions. METHODS AND RESULTS Normal mucosal fibroblasts (NFs) and OLP associated-fibroblasts (OLP AFs) were isolated from the oral mucosa of 15 healthy controls and 30 OLP patients. We detected the expression of miR-155-5p and fibroblast activation protein alpha (FAP-α) using quantitative RT-PCR and analyzed their correlation. Interleukin (IL)-6 and IL-8 levels were determined using ELISA. Expression of suppressor of cytokine signaling (SOCS) 1 was analyzed by western blotting. A dual-luciferase reporter assay was performed to investigate the interaction between miR-155-5p and SOCS1. MiR-155-5p and FAP-α were significantly increased and positively correlated in OLP AFs. Overexpression of miR-155-5p in OLP AFs augmented IL-6 and IL-8 release and decreased SOCS1 expression, whereas knockdown of miR-155-5p in OLP AFs decreased IL-6 and IL-8 release. The expression of SOCS1 was downregulated in OLP AFs, and SOCS1 silencing augmented IL-6 and IL-8 production in OLP AFs. Furthermore, miR-155-5p inhibited SOCS1 expression by directly targeting its 3'-UTR in OLP AFs. CONCLUSIONS MiR-155-5p regulates the secretion of IL-6 and IL-8 by downregulating the expression of SOCS1 in activated OLP AFs. Our results provide novel insights into the pathogenesis of OLP and identify a potential new target for OLP therapy.
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Affiliation(s)
- Juehua Cheng
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yuyao Zhang
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Jingjing Yang
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yanting Wang
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Juanyong Xu
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yuan Fan
- Department of Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. .,Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. .,Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.
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LNCRNA XIST Inhibits miR-377-3p to Hinder Th17 Cell Differentiation through Upregulating ETS1. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:6545834. [PMID: 35747716 PMCID: PMC9213139 DOI: 10.1155/2022/6545834] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 02/08/2023]
Abstract
Background Th17 cell differentiation is involved in the development and progression of many diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Present study mainly focused on the role of LINC-XIST in Th17 cell differentiation. Methods The naïve CD4+ T cells were isolated from human whole blood. Cells were cultured under Th17 cell-polarizing condition for 6 days. The expression of LINC-XIST and miR-153-3p was measured by qPCR. The relationship between LINC-XIST, miR-153-3p, and ETS1 was predicted by TargetScan website and authenticated by luciferase reporter assay. ELISA assays were conducted to evaluate the IL-17 concentration. Western blot was utilized to measure the protein expression of ETS1. Th17 cell frequency was examined by flow cytometry. Results The expression of XIST markedly decreased and miR-153-3p expression markedly increased with Th17 cell differentiation. The mRNA expression of IL-17, IL-17 concentration, and Th17 cell frequency were observably decreased in overexpressed LINC-XIST group. Luciferase reporter assay authenticated that miR-153-5p was directly regulated by LINC-XIST. miR-153-3p inhibitor observably decreased IL-17 concentration, mRNA expression of IL-17, and Th17 cell frequency while si-XIST reversed this impact. ETS1 was confirmed to be regulated by miR-153-5p via luciferase reporter assay. In addition, ETS1 markedly decreased IL-17 mRNA expression, IL-17 concentration, and Th17 cell frequency while miR-153-5p mimic reversed this impact. Conclusion LNCRNA XIST inhibited miR-377-3p to hinder Th17 cell differentiation through upregulating ETS1.
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Masuzaki R, Kanda T, Sasaki R, Matsumoto N, Nirei K, Ogawa M, Karp SJ, Moriyama M, Kogure H. Suppressors of Cytokine Signaling and Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:2549. [PMID: 35626153 PMCID: PMC9139988 DOI: 10.3390/cancers14102549] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 05/21/2022] [Indexed: 12/13/2022] Open
Abstract
Cytokines are secreted soluble glycoproteins that regulate cellular growth, proliferation, and differentiation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate cytokine signaling and form a classical negative feedback loop in the signaling pathways. There are eight members of the SOCS family. The SOCS proteins are all comprised of a loosely conserved N-terminal domain, a central Src homology 2 (SH2) domain, and a highly conserved SOCS box at the C-terminus. The role of SOCS proteins has been implicated in the regulation of cytokines and growth factors in liver diseases. The SOCS1 and SOCS3 proteins are involved in immune response and inhibit protective interferon signaling in viral hepatitis. A decreased expression of SOCS3 is associated with advanced stage and poor prognosis of patients with hepatocellular carcinoma (HCC). DNA methylations of SOCS1 and SOCS3 are found in HCC. Precise regulation of liver regeneration is influenced by stimulatory and inhibitory factors after partial hepatectomy (PH), in particular, SOCS2 and SOCS3 are induced at an early time point after PH. Evidence supporting the important role of SOCS signaling during liver regeneration also supports a role of SOCS signaling in HCC. Immuno-oncology drugs are now the first-line therapy for advanced HCC. The SOCS can be potential targets for HCC in terms of cell proliferation, cell differentiation, and immune response. In this literature review, we summarize recent findings of the SOCS family proteins related to HCC and liver diseases.
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Affiliation(s)
- Ryota Masuzaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (K.N.); (M.O.); (M.M.); (H.K.)
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (K.N.); (M.O.); (M.M.); (H.K.)
| | - Reina Sasaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (K.N.); (M.O.); (M.M.); (H.K.)
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (K.N.); (M.O.); (M.M.); (H.K.)
| | - Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (K.N.); (M.O.); (M.M.); (H.K.)
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (K.N.); (M.O.); (M.M.); (H.K.)
| | - Seth J. Karp
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (K.N.); (M.O.); (M.M.); (H.K.)
| | - Hirofumi Kogure
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (K.N.); (M.O.); (M.M.); (H.K.)
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Devvanshi H, Kachhwaha R, Manhswita A, Bhatnagar S, Kshetrapal P. Immunological Changes in Pregnancy and Prospects of Therapeutic Pla-Xosomes in Adverse Pregnancy Outcomes. Front Pharmacol 2022; 13:895254. [PMID: 35517798 PMCID: PMC9065684 DOI: 10.3389/fphar.2022.895254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 03/31/2022] [Indexed: 11/13/2022] Open
Abstract
Stringent balance of the immune system is a key regulatory factor in defining successful implantation, fetal development, and timely parturition. Interference in these primary regulatory mechanisms, either at adolescence or prenatal state led to adverse pregnancy outcomes. Fertility restoration with the help of injectable gonadotrophins/progesterone, ovulation-inducing drugs, immunomodulatory drugs (corticosteroids), and reproductive surgeries provides inadequate responses, which manifest its own side effects. The development of a potential diagnostic biomarker and an effectual treatment for adverse pregnancy outcomes is a prerequisite to maternal and child health. Parent cell originated bi-layered-intraluminal nano-vesicles (30-150 nm) also known as exosomes are detected in all types of bodily fluids like blood, saliva, breast milk, urine, etc. Exosomes being the most biological residual structures with the least cytotoxicity are loaded with cargo in the form of RNAs (miRNAs), proteins (cytokines), hormones (estrogen, progesterone, etc.), cDNAs, and metabolites making them chief molecules of cell-cell communication. Their keen involvement in the regulation of biological processes has portrayed them as the power shots of cues to understand the disease's pathophysiology and progression. Recent studies have demonstrated the role of immunexosomes (immunomodulating exosomes) in maintaining unwavering immune homeostasis between the mother and developing fetus for a healthy pregnancy. Moreover, the concentration and size of the exosomes are extensively studied in adverse pregnancies like preeclampsia, gestational diabetes mellitus (GDM), and preterm premature rupture of membrane (pPROMs) as an early diagnostic marker, thus giving in-depth information about their pathophysiology. Exosomes have also been engineered physically as well as genetically to enhance their encapsulation efficiency and specificity in therapy for cancer and adverse pregnancies. Successful bench to bedside discoveries and interventions in cancer has motivated developmental biologists to investigate the role of immunexosomes and their active components. Our review summarizes the pre-clinical studies for the use of these power-shots as therapeutic agents. We envisage that these studies will pave the path for the use of immunexosomes in clinical settings for reproductive problems that arise due to immune perturbance in homeostasis either at adolescence or prenatal state.
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Affiliation(s)
- Himadri Devvanshi
- Maternal and Child Health, Translational Health Science and Technology Institute, Faridabad, India
| | - Rohit Kachhwaha
- Maternal and Child Health, Translational Health Science and Technology Institute, Faridabad, India
| | - Anima Manhswita
- School of Agriculture and Food Science, The University of Queensland, Brisbane, QLD, Australia
| | - Shinjini Bhatnagar
- Maternal and Child Health, Translational Health Science and Technology Institute, Faridabad, India
| | - Pallavi Kshetrapal
- Maternal and Child Health, Translational Health Science and Technology Institute, Faridabad, India
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Czaja AJ. Examining micro-ribonucleic acids as diagnostic and therapeutic prospects in autoimmune hepatitis. Expert Rev Clin Immunol 2022; 18:591-607. [PMID: 35510750 DOI: 10.1080/1744666x.2022.2074839] [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: 02/07/2023]
Abstract
INTRODUCTION Micro-ribonucleic acids modulate the immune response by affecting the post-transcriptional expression of genes that influence the proliferation and function of activated immune cells, including regulatory T cells. Individual expressions or patterns in peripheral blood and liver tissue may have diagnostic value, reflect treatment response, or become therapeutic targets. The goals of this review are to present the properties and actions of micro-ribonucleic acids, indicate the key individual expressions in autoimmune hepatitis, and describe prospective clinical applications in diagnosis and management. AREAS COVERED Abstracts were identified in PubMed using the search words "microRNAs", "microRNAs in liver disease", and "microRNAs in autoimmune hepatitis". The number of abstracts reviewed exceeded 2000, and the number of full-length articles reviewed was 108. EXPERT OPINION Individual micro-ribonucleic acids, miR-21, miR-122, and miR-155, have been associated with biochemical severity, histological grade of inflammation, and pivotal pathogenic mechanisms in autoimmune hepatitis. Antisense oligonucleotides that down-regulate deleterious individual gene expressions, engineered molecules that impair targeting of gene products, and drugs that non-selectively up-regulate the biogenesis of potentially deficient gene regulators are feasible treatment options. Micro-ribonucleic acids constitute an under-evaluated area in autoimmune hepatitis that promises to improve diagnosis, pathogenic concepts, and therapy.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Jung B, Ferrer G, Chiu PY, Aslam R, Ng A, Palacios F, Wysota M, Cardillo M, Kolitz JE, Allen SL, Barrientos JC, Rai KR, Chiorazzi N, Sherry B. Activated CLL cells regulate IL17F producing Th17 cells in miR155 dependent and outcome specific manners. JCI Insight 2022; 7:158243. [PMID: 35511436 DOI: 10.1172/jci.insight.158243] [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] [Received: 01/06/2022] [Accepted: 05/04/2022] [Indexed: 11/17/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) results from expansion of a CD5+ B-cell clone that requires interactions with other cell types, including T cells. Moreover, CLL patients have elevated circulating IL17A+ and IL17F+ CD4+ T cells (Th17s), with higher IL17A+Th17s correlating with better outcomes. We report that CLL Th17s express more miR155, a Th17 differentiation regulator, than control Th17s, despite naïve CD4+ T cell (TN) basal miR155 levels being similar in both. We also found that CLL cells directly regulate miR155 levels in TN, thereby affecting Th17 differentiation by documenting that: co-culturing TN with resting (Brest) or activated (Bact) CLL cells alters the magnitude and direction of T-cell miR155 levels; CLL Bact promote IL17A+ and IL17F+ T cell generation by a miR155-dependent mechanism, confirmed by miR155 inhibition; co-cultures of TN with CLL Bact lead to a linear correlation between the degree and direction of T-cell miR155 expression changes and IL17F production, but not IL17A; Bact-mediated changes in TN miR155 expression correlate with outcome, irrespective of IGHV mutation status, a strong prognostic indicator. Together, the results identify a previously unrecognized CLL Bact-dependent mechanism, upregulation of TN miR155 expression and subsequent enhancement of IL17F+ Th17 generation, that favors better clinical courses.
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Affiliation(s)
- Byeongho Jung
- Karches Center for Oncology Research, Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, United States of America
| | - Gerardo Ferrer
- Karches Center for Oncology Research, Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, United States of America
| | - Pui Yan Chiu
- Karches Center for Oncology Research, Institute of Molecular Medicine, The Feinstein Insitute for Medical Research, Manhasset, United States of America
| | - Rukhsana Aslam
- Karches Center for Oncology Research, Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, United States of America
| | - Anita Ng
- Karches Center for Oncology Research, Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, United States of America
| | - Florencia Palacios
- Karches Center for Oncology Research, Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, United States of America
| | - Michael Wysota
- Karches Center for Oncology Research, Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, United States of America
| | - Martina Cardillo
- Karches Center for Oncology Research, Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, United States of America
| | - Jonathan E Kolitz
- Department of Medicine, Northwell Health, New Hyde Park, United States of America
| | - Steven L Allen
- Department of Medicine, Northwell Health, New Hyde Park, United States of America
| | | | - Kanti R Rai
- Karches Center for Oncology Research, Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, United States of America
| | - Nicholas Chiorazzi
- Karches Center for Oncology Research, Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, United States of America
| | - Barbara Sherry
- Center for Immunology & Inflammation, Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, United States of America
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Jiang Q, Li Y, Wu Q, Huang L, Xu J, Zeng Q. Pathogenic role of microRNAs in atherosclerotic ischemic stroke: Implications for diagnosis and therapy. Genes Dis 2022; 9:682-696. [PMID: 35782982 PMCID: PMC9243347 DOI: 10.1016/j.gendis.2021.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 12/16/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke resulting from atherosclerosis (particularly in the carotid artery) is one of the major subtypes of stroke and has a high incidence of death. Disordered lipid homeostasis, lipid deposition, local macrophage infiltration, smooth muscle cell proliferation, and plaque rupture are the main pathological processes of atherosclerotic ischemic stroke. Hepatocytes, macrophages, endothelial cells and vascular smooth muscle cells are the main cell types participating in these processes. By inhibiting the expression of the target genes in these cells, microRNAs play a key role in regulating lipid disorders and atherosclerotic ischemic stroke. In this article, we listed the microRNAs implicated in the pathology of atherosclerotic ischemic stroke and aimed to explain their pro- or antiatherosclerotic roles. Our article provides an update on the potential diagnostic use of miRNAs for detecting growing plaques and impending clinical events. Finally, we provide a perspective on the therapeutic use of local microRNA delivery and discuss the challenges for this potential therapy.
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Benazzo A, Bozzini S, Auner S, Berezhinskiy HO, Watzenboeck ML, Schwarz S, Schweiger T, Klepetko W, Wekerle T, Hoetzenecker K, Meloni F, Jaksch P. Differential expression of circulating miRNAs after alemtuzumab induction therapy in lung transplantation. Sci Rep 2022; 12:7072. [PMID: 35490174 PMCID: PMC9056512 DOI: 10.1038/s41598-022-10866-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 04/13/2022] [Indexed: 11/17/2022] Open
Abstract
Alemtuzumab is a monoclonal antibody targeting CD52, used as induction therapy after lung transplantation (LTx). Its engagement produces a long-lasting immunodepletion; however, the mechanisms driving cell reconstitution are poorly defined. We hypothesized that miRNAs are involved in this process. The expression of a set of miRNAs, cytokines and co-signaling molecules was measured with RT-qPCR and flow cytometry in prospectively collected serum samples of LTx recipients, after alemtuzumab or no induction therapy. Twenty-six LTx recipients who received alemtuzumab and twenty-seven matched LTx recipients without induction therapy were included in the analysis. One year after transplantation four miRNAs were differentially regulated: miR-23b (p = 0.05) miR-146 (p = 0.04), miR-155 (p < 0.001) and miR-486 (p < 0.001). Expression of 3 miRNAs changed within the alemtuzumab group: miR-146 (p < 0.001), miR-155 (p < 0.001) and miR-31 (p < 0.001). Levels of IL-13, IL-4, IFN-γ, BAFF, IL-5, IL-9, IL-17F, IL-17A and IL-22 were different one year after transplantation compared to baseline. In no-induction group, concentration of sCD27, sB7.2 and sPD-L1 increased overtime. Expression of miR-23b, miR-146, miR-486, miR-155 and miR-31 was different in LTx recipients who received alemtuzumab compared to recipients without induction therapy. The observed cytokine pattern suggested proliferation of specific B cell subsets in alemtuzumab group and co-stimulation of T-cells in no-induction group.
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Affiliation(s)
- A Benazzo
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
- Department of Thoracic Surgery, Lung Transplantation Research Lab, Medical University of Vienna, Vienna, Austria.
- Division of Thoracic Surgery, Medical University of Vienna, Währinger Guertel 18-20, 1090, Vienna, Austria.
| | - S Bozzini
- Department of Internal Medicine, Unit of Respiratory Diseases, Laboratory of Cell Biology and Immunology, University of Pavia and IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | - S Auner
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
- Department of Thoracic Surgery, Lung Transplantation Research Lab, Medical University of Vienna, Vienna, Austria
| | - H Oya Berezhinskiy
- Department of Thoracic Surgery, Lung Transplantation Research Lab, Medical University of Vienna, Vienna, Austria
| | - M L Watzenboeck
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - S Schwarz
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - T Schweiger
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - W Klepetko
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - T Wekerle
- Section of Transplantation Immunology, Division of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - K Hoetzenecker
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - F Meloni
- Department of Internal Medicine, Unit of Respiratory Diseases, Laboratory of Cell Biology and Immunology, University of Pavia and IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | - P Jaksch
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
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Li T, Liu W, Hui W, Shi T, Liu H, Feng Y, Gao F. Integrated Analysis of Ulcerative Colitis Revealed an Association between PHLPP2 and Immune Infiltration. DISEASE MARKERS 2022; 2022:4983471. [PMID: 35308140 PMCID: PMC8931176 DOI: 10.1155/2022/4983471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/08/2022] [Accepted: 02/17/2022] [Indexed: 02/07/2023]
Abstract
Ulcerative colitis (UC) is a progressive intestine inflammatory disease that is prone to recur. Herein, we utilize microarray technology and bioinformatics to reveal the underlying pathogenesis of UC and provide novel markers. Colonic biopsies were taken from eight UC patients and eight healthy controls. Three differentially expressed miRNAs (DEMIs) and 264 differentially expressed genes (DEGs) were screened using mRNA and miRNA microarray. Most DEGs were significantly associated with immune response and were markedly enriched in the IL-17 signaling pathway. Among the target genes of DEMIs, PHLPP2 overlapped with DEGs and the downregulation of PHLPP2 group was mainly involved in the epithelial-mesenchymal transition. PHLPP2 was downregulated in UC patients, which was validated in 5 GEO datasets and qRT-PCR. The ROC curve demonstrated that PHLPP2 has a perfect ability to distinguish UC patients from healthy controls. Moreover, PHLPP2 was low expression in patients with active UC. CIBERSORT algorithm indicated that the abundance of gamma delta T cells (P = 0.04), M0 macrophages (P = 0.01), and activated mast cells (P < 0.01) was significantly greater than that of the control group. The Spearman correlation analysis showed that PHLPP2 was positively correlated with the proportion of activated NK cells (rho = 0.62, P = 0.013) and Tregs (rho = 0.55, P = 0.03), but negatively correlated with those of activated mast cells (rho = -0.8, P < 0.01) and macrophages (rho = -0.73, P < 0.01). These results indicate that PHLPP2 is associated with immune cells in the pathogenesis of UC, as well as provide new prospects and future directions of investigation.
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Affiliation(s)
- Ting Li
- Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Weidong Liu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Wenjia Hui
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Tian Shi
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Huan Liu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Yan Feng
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
| | - Feng Gao
- Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, China
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Barghbani M, Sarookhani MR, Abbasi M, Maali A, Hajiaghaei M, Keshavarz Shahbaz S, Foroughi F. Evaluation of serum level of miR-155 and TNF-α in rheumatoid arthritis patients. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2021.101447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Wang F, Yang Y, Li Z, Wang Y, Zhang Z, Zhang W, Mu Y, Yang J, Yu L, Wang M. Mannan-Binding Lectin Regulates the Th17/Treg Axis Through JAK/STAT and TGF-β/SMAD Signaling Against Candida albicans Infection. J Inflamm Res 2022; 15:1797-1810. [PMID: 35300210 PMCID: PMC8923702 DOI: 10.2147/jir.s344489] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 03/08/2022] [Indexed: 12/04/2022] Open
Abstract
Background Mannan-binding lectin (MBL) is a key molecule in innate immunity and activates the lectin complement pathway, which plays an important role in resisting Candida albicans (C. albicans) infection. However, the underlying mechanism of this resistance to infection remains unclear. Methods In this study, we investigated how MBL regulates the differentiation of CD4+ T cells into T helper type 17 (Th17) and T regulatory (Treg) cells against C. albicans in mice, as well as the underlying mechanisms. We generated MBL double-knockout (KO) mice and infected them with C. albicans by intraperitoneal injection. Results Compared with that in wild-type (WT) mice, the percentage of Th17 cells increased in MBL-null mice, whereas Treg cells decreased, indicating that MBL might regulate the Th17/Treg balance. In addition, in MBL-null mice, the expression levels of interleukin (IL)-17A, IL-21, and the master transcription factor of Th17 cells, RORγt, significantly increased. Conversely, IL-10, IL-2, and the Treg-specific transcription factor, Foxp3, decreased. Moreover, we found that the levels of TGF-β and IL-6 upregulated in MBL-null mice. Mechanistically, we found that MBL regulated the TGF-β/SMAD pathway through the inhibition of p-SMAD2 and promotion of p-SMAD3, and mediated the JAK/STAT pathway through the inhibition of p-JAK2 and p-STAT3 and promotion of p-JAK3 and p-STAT5. MBL double-KO mice showed a more severe inflammatory response and significantly lower survival rates with C. albicans infection. Conclusion These results suggest that MBL regulates the Th17/Treg cell balance to inhibit inflammatory responses, possibly via IL-6- and TGF-β-mediated JAK/STAT and TGF-β/SMAD signaling, and play an important role in anti-C. albicans infection.
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Affiliation(s)
- Fanping Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
| | - Yonghui Yang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Henan Center for Disease Control and Prevention, Zhengzhou, Henan, 450000, People’s Republic of China
| | - Zhixin Li
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
| | - Yan Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Department of Laboratory Medicine, Luoyang Oriental Hospital, Luoyang, Henan, 471000, People’s Republic of China
| | - Zhenchao Zhang
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Wei Zhang
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Yonghui Mu
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Jingwen Yang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
| | - Lili Yu
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Mingyong Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- Correspondence: Mingyong Wang; Lili Yu, Email ;
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Perdaens O, van Pesch V. Molecular Mechanisms of Immunosenescene and Inflammaging: Relevance to the Immunopathogenesis and Treatment of Multiple Sclerosis. Front Neurol 2022; 12:811518. [PMID: 35281989 PMCID: PMC8913495 DOI: 10.3389/fneur.2021.811518] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 12/27/2021] [Indexed: 12/18/2022] Open
Abstract
Aging is characterized, amongst other features, by a complex process of cellular senescence involving both innate and adaptive immunity, called immunosenescence and associated to inflammaging, a low-grade chronic inflammation. Both processes fuel each other and partially explain increasing incidence of cancers, infections, age-related autoimmunity, and vascular disease as well as a reduced response to vaccination. Multiple sclerosis (MS) is a lifelong disease, for which considerable progress in disease-modifying therapies (DMTs) and management has improved long-term survival. However, disability progression, increasing with age and disease duration, remains. Neurologists are now involved in caring for elderly MS patients, with increasing comorbidities. Aging of the immune system therefore has relevant implications for MS pathogenesis, response to DMTs and the risks mediated by these treatments. We propose to review current evidence regarding markers and molecular mechanisms of immunosenescence and their relevance to understanding MS pathogenesis. We will focus on age-related changes in the innate and adaptive immune system in MS and other auto-immune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The consequences of these immune changes on MS pathology, in interaction with the intrinsic aging process of central nervous system resident cells will be discussed. Finally, the impact of immunosenescence on disease evolution and on the safety and efficacy of current DMTs will be presented.
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Affiliation(s)
- Océane Perdaens
- Laboratory of Neurochemistry, Institute of Neuroscience, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Vincent van Pesch
- Laboratory of Neurochemistry, Institute of Neuroscience, Université catholique de Louvain (UCLouvain), Brussels, Belgium
- Department of Neurology, Cliniques universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), Brussels, Belgium
- *Correspondence: Vincent van Pesch
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Zhou F, Wang X, Wang L, Sun X, Tan G, Wei W, Zheng G, Ma X, Tian D, Yu H. Genetics, Epigenetics, Cellular Immunology, and Gut Microbiota: Emerging Links With Graves' Disease. Front Cell Dev Biol 2022; 9:794912. [PMID: 35059400 PMCID: PMC8765724 DOI: 10.3389/fcell.2021.794912] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/09/2021] [Indexed: 11/13/2022] Open
Abstract
Graves’ disease (GD) is a well-known organ-specific autoimmune disease characterized by hyperthyroidism, goiter, and exophthalmos. The incidence of GD is approximately 2.0–3.0% in China and 0.5–2.0% in Western countries. Due to the complex pathogenesis and etiology of GD, current treatment methods have great side effects that seriously endanger human health. Therefore, it is particularly important to understand the pathogenesis of GD. Various studies have shown that genetics, epigenetics, cellular immunology, and gut microbiota are all involved in the development of GD. Genetically, CD25 gene and VDR gene polymorphisms are involved in the development of GD by increasing the ratio of Th17/Treg cells. Epigenetically, miR-23a-3p and lncRNA-MEG3 lead to Th17/Treg imbalance and participate in the progression of GD. Moreover, commensal microbe deletion can disrupt Th17/Treg balance and participate in the occurrence of GD. The imbalance of Th17/Treg cells induced by genetics, epigenetics, and gut microbiota plays a vital role in the pathogenesis of GD. Therefore, this article reviews the role of genetics, epigenetics, cellular immunology, and gut microbiota in the pathogenic mechanism of GD. This may lead to the development of novel therapeutic strategies and providing promising therapeutic targets.
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Affiliation(s)
- Fangyu Zhou
- Department of Immunology, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Xin Wang
- School of Basic Medical Sciences, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Lingjun Wang
- School of Basic Medical Sciences, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Xin Sun
- School of Basic Medical Sciences, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Guiqin Tan
- Department of Immunology, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Wenwen Wei
- Department of Immunology, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Guangbing Zheng
- Department of Immunology, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Xiaomin Ma
- Department of Immunology, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Dan Tian
- Department of Immunology, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Hongsong Yu
- Department of Immunology, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, China
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50
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Diaz-Garrido N, Badia J, Baldomà L. Modulation of Dendritic Cells by Microbiota Extracellular Vesicles Influences the Cytokine Profile and Exosome Cargo. Nutrients 2022; 14:nu14020344. [PMID: 35057528 PMCID: PMC8778470 DOI: 10.3390/nu14020344] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 12/12/2022] Open
Abstract
Gut bacteria release extracellular vesicles (BEVs) as an intercellular communication mechanism that primes the host innate immune system. BEVs from E. coli activate dendritic cells (DCs) and subsequent T-cell responses in a strain-specific manner. The specific immunomodulatory effects were, in part, mediated by differential regulation of miRNAs. This study aimed to deepen understanding of the mechanisms of BEVs to drive specific immune responses by analyzing their impact on DC-secreted cytokines and exosomes. DCs were challenged with BEVs from probiotic and commensal E. coli strains. The ability of DC-secreted factors to activate T-cell responses was assessed by cytokine quantification in indirect DCs/naïve CD4+ T-cells co-cultures on Transwell supports. DC-exosomes were characterized in terms of costimulatory molecules and miRNAs cargo. In the absence of direct cellular contacts, DC-secreted factors triggered secretion of effector cytokines by T-cells with the same trend as direct DC/T-cell co-cultures. The main differences between the strains influenced the production of Th1- and Treg-specific cytokines. Exosomes released by BEV-activated DCs were enriched in surface proteins involved in antigen presentation and T-cell activation, but differed in the content of immune-related miRNA, depending on the origin of the BEVs. These differences were consistent with the derived immune responses.
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Affiliation(s)
- Natalia Diaz-Garrido
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
- Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Josefa Badia
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
- Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Laura Baldomà
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
- Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
- Correspondence:
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