Immunological Investigations最新文献

{"title":"Myelin-Reactive TCR/IgM Dual-Expresser Lymphocytes in Multiple Sclerosis: Linking Pathogenesis to Anti-CD20 Therapy.","authors":"Prajita Paul, Marjan Behzadirad, Rafid Al Hallaf, Susana C Dominguez-Penuela, Carlos A Pardo, Chunfa Jie, Bardia Nourbakhsh, Abdel Rahim A Hamad","doi":"10.1080/08820139.2025.2552841","DOIUrl":"https://doi.org/10.1080/08820139.2025.2552841","url":null,"abstract":"<p><strong>Background: </strong>Multiple sclerosis (MS) is an autoimmune disorder driven by myelin autoantigen-specific autoreactive T cells, yet the most effective disease-modifying therapies (DMTs) target B cells. The mechanism underlying this paradox remains unclear. Here, we identify dual-expressor cells (DEs) -a novel lymphocyte population with hybrid T and B cell characteristics, including co-expression of the T cell receptors (TCRαβ) and surface B cell receptors (BCRs), primarily IgM-as potential contributors to MS pathogenesis and inadvertent targets of anti-CD20 DMTs.</p><p><strong>Methods: </strong>DEs were examined in the peripheral blood and cerebrospinal fluid (CSF) of patients with relapsing-remitting MS (RRMS) compared to healthy controls. Their phenotype and functional properties were characterized, including responses to myelin autoantigens and susceptibility to depletion in a pilot cohort of seven RRMS patients treated with ocrelizumab.</p><p><strong>Results: </strong>DEs were found at significantly higher frequencies in the peripheral blood of patients with RRMS compared to healthy controls and were further enriched in CSF, where up to 95% expressed CD20, versus ~60% in blood. Furthermore, most of DEs in CSF express CXCR3, indicating involvement of CXCR3-CCL-9, 10 and 11 in their recruiting and maintenance in the CSF of MS patients. Functionally, DEs exhibited robust responses to myelin autoantigens, supporting their relevance in disease. In a pilot cohort of seven RRMS patients, ocrelizumab significantly reduced circulating DE frequencies, confirming their susceptibility to CD20-mediated depletion.</p><p><strong>Conclusions: </strong>These findings implicate DEs in MS and provide insight into the efficacy of anti-CD20 therapies in a traditionally T cell-driven disease.</p>","PeriodicalId":13387,"journal":{"name":"Immunological Investigations","volume":" ","pages":"1-19"},"PeriodicalIF":2.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanism of Butyrate Modulating Treg/Th17 Balance in UC Through cAMP-PKA/mTOR Axis.","authors":"Minhao Li, Tinglong Wang, Mei Yuan","doi":"10.1080/08820139.2025.2556790","DOIUrl":"https://doi.org/10.1080/08820139.2025.2556790","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to elucidate how butyrate, a short-chain fatty acid, regulates the Treg/Th17 balance in ulcerative colitis (UC) via the cAMP-PKA/mTOR signaling pathway, offering novel treatment strategies.</p><p><strong>Methods: </strong>Dextran sulfate sodium (DSS) was used to induce ulcerative colitis in a mouse model. Various butyrate dosages were administered to the mice. The mice's body weight, colon length, spleen index (SI), and disease activity index (DAI) were all assessed.HE staining and Masson staining were used for histopathological evaluation. Immunohistochemistry and RT-qPCR were applied to detect fibrosis markers. Flow cytometry, RT-qPCR, and ELISA were employed to analyze immune cell subsets and cytokines. RT-qPCR and Western blotting were utilized to explore the cAMP-PKA/mTOR signaling pathway. Specific inhibitors were used to further confirm the mechanism of its action.</p><p><strong>Results: </strong>Butyrate treatmentreduced DAI and SI, and reversed pathological changes (weight loss, colon shortening, splenomegaly) in DSS-induced UC model mice, with the high-dose group showing the best recovery. It inhibited colon fibrosis,and decreased fibrosis markers. By regulating the regulatory T cell (Treg)/T helper 17 cell (Th17) balance, butyrate restored immune homeostasis. Flow cytometry showed DSS-induced immune imbalance was reversed in a dose-dependent manner. Additionally, butyrate modulated the cAMP-PKA/mTOR signaling pathway, reversing DSS-induced gene and protein expression changes. Specific inhibitor experiments confirmed that butyrate exerted its therapeutic effects via this pathway.</p><p><strong>Conclusion: </strong>Butyrate can markedly alleviate acute UC intestinal inflammation and block chronic fibrosis progression. The bidirectional regulation of the cAMP-PKA/mTOR signaling pathway is the key mechanism for butyrate to restore immune homeostasis.</p>","PeriodicalId":13387,"journal":{"name":"Immunological Investigations","volume":" ","pages":"1-23"},"PeriodicalIF":2.4,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Pulmonary Neuroendocrine Cells in COPD.","authors":"Lulu Zhang, Bo Tu, Qingliang Xue","doi":"10.1080/08820139.2025.2547690","DOIUrl":"https://doi.org/10.1080/08820139.2025.2547690","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary neuroendocrine cells (PNECs) are specialized airway epithelial cells with dual sensory and secretory functions. They release bioactive mediators --including neuropeptides such as calcitonin gene-related peptide (CGRP) and gastrin-releasing peptide (GRP), and neurotransmitters such as 5-hydroxytryptamine (5-HT) and γ-aminobutyric acid (GABA) --that regulate airway smooth-muscle tone, mucus production, and immune responses. In chronic obstructive pulmonary disease (COPD), these PNEC-derived mediators contribute to airway inflammation, remodeling, and smooth-muscle dysfunction. Chronic inflammation and oxidative stress in COPD are closely linked to PNEC activity.</p><p><strong>Methods: </strong>We conducted a narrative review summarizing evidence on PNEC biology, their principal secretory mediators, and mechanistic links to key pathological processes in COPD, including inflammation, oxidative stress, and airway remodeling.</p><p><strong>Results: </strong>PNEC-derived mediators (CGRP, GRP, 5-HT, GABA) participate in COPD-relevant processes by modulating airway tone, mucus production, and immune responses. In COPD, dysregulated PNEC activity is associated with persistent inflammation, heightened oxidative stress, airway remodeling, and smooth-muscle dysfunction. PNECs also contribute to epithelial repair and regeneration, indicating a role in maintaining -and, when perturbed, disrupting -airway homeostasis.</p><p><strong>Conclusion: </strong>PNECs integrate sensory inputs with secretory signaling to shape multiple COPD-related pathways. Clarifying the mechanisms and context dependence of PNEC activity may inform therapeutic strategies targeting PNEC-derived mediators and support the development of novel interventions for COPD.</p>","PeriodicalId":13387,"journal":{"name":"Immunological Investigations","volume":" ","pages":"1-15"},"PeriodicalIF":2.4,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TCR/BCR Secondary Rearrangement in Autoimmune Diseases: Molecular Mechanisms, Pathogenic Roles, and Therapeutic Frontiers.","authors":"Fei Yang, Biao Zhang, Yi Liu, Zhihui Feng, Yujiao Xu, Zipeng Hu, Chunhong Li, Chune Mo, Jingquan He, Songbai Liao, Xianliang Hou","doi":"10.1080/08820139.2025.2556781","DOIUrl":"https://doi.org/10.1080/08820139.2025.2556781","url":null,"abstract":"<p><p>Autoimmune diseases (AIDs) constitute a group of disorders where the immune system mistakenly attacks the body's tissues. The pathogenesis of AIDs involve a breakdown in immune tolerance, culminating in an immune response that targets autoantigens. In adaptive immunity, secondary rearrangement of T cell receptors (TCRs) and B cell receptors (BCRs) involves sequential V(D)J recombination events during lymphocyte development. Imperfect receptor editing during this process can generate autoreactive clones, thereby contributing to the pathogenesis of AIDs. Emerging evidence implicates secondary V(D)J recombination in TCR and BCR genes as a pathogenic driver in multiple AIDs. The detection of secondary rearrangements, along with targeted therapeutic interventions (e.g. anti-CD40L, IL6), offers novel avenues for the early prediction and diagnosis of these diseases. This article provides a comprehensive overview of the current research on the role of TCR/BCR secondary rearrangements in AIDs, elucidating their mechanisms of action to enhance our understanding of the pathogenesis, diagnosis, and treatment of autoimmune disorders.</p>","PeriodicalId":13387,"journal":{"name":"Immunological Investigations","volume":" ","pages":"1-22"},"PeriodicalIF":2.4,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biased Usage of V/D/J Genes and Clonal Diversity in IgG Repertoires Correlates with Disease Activity and Clinical Features in Systemic Autoimmune Diseases.","authors":"Qian Wang, Delong Feng, Yang Song, Zhi Hu, Qianjin Lu, Ming Zhao","doi":"10.1080/08820139.2025.2550374","DOIUrl":"https://doi.org/10.1080/08820139.2025.2550374","url":null,"abstract":"<p><strong>Objective: </strong>To examine whether features of the B cell receptor (BCR) IgG repertoire correlate with disease activity and clinical phenotypes in systemic autoimmune diseases (SAIDs).</p><p><strong>Methods: </strong>High-throughput sequencing was performed on IgG heavy chain repertoires from 138 patients with SAIDs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma (SSc), and idiopathic inflammatory myopathy (IIM), as well as 36 healthy controls (HC). We analyzed V/D/J gene usage, clonal distribution and diversity, CDR3 length distribution and amino acid usage, and the correlation between specific BCR features and clinical features.</p><p><strong>Results: </strong>SAIDs showed skewed usage of V/D/J genes and V-D-J combinations, with altered CDR3 length distributions and amino acid usage in SLE, RA, SSc, and IIM. Notably, SLE and RA exhibited a pronounced expansion of mid-ranked clones and significantly higher clonal diversity compared to HC. Specific genes, including IGHD2-15, IGHV1-24, IGHV1-69-2, IGHV1-8, and IGHV4 family members, along with increased clonal diversity, were closely associated with disease activity and clinical phenotypes in SLE and RA.</p><p><strong>Conclusions: </strong>IgG repertoire features reflect disease-related immune perturbations and may serve as potential biomarkers for disease progression, diagnostics and targeted therapies in SAIDs.</p>","PeriodicalId":13387,"journal":{"name":"Immunological Investigations","volume":" ","pages":"1-21"},"PeriodicalIF":2.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Dichotomous Role of Tertiary Lymphoid Structures in Hepatocellular Carcinoma: From Spatial Location to Clinical Implications.","authors":"Jingyi Xu, Yunzhang Cheng, Yun Feng, Yilin Wang","doi":"10.1080/08820139.2025.2553774","DOIUrl":"10.1080/08820139.2025.2553774","url":null,"abstract":"<p><strong>Background: </strong>Tertiary lymphoid structures (TLSs) function as ectopic immune centers in non-lymphoid tissues and are a key area of research in tumor immunology, particularly in hepatocellular carcinoma (HCC). However, the role of TLSs in HCC shows significant heterogeneity; intratumoral TLSs (iTLSs) are linked to favorable outcomes and immune therapy responses, while peritumoral TLSs may be dysfunctional or promote tumor progression. This spatial paradox is a core scientific question for understanding and leveraging TLSs in HCC treatment. The liver's unique immunosuppressive and fibrotic microenvironment, influenced by hepatic stellcell-derived cancer-associated fibroblasts (CAFs) and local signals like tryptophan metabolism, profoundly regulates TLSs formation and functional polarization.</p><p><strong>Methods: </strong>This review integrates current research on TLSs in HCC, focusing on their functional heterogeneity based on spatial localization and the regulatory mechanisms involving the liver's microenvironment. It identifies major bottlenecks in TLSs clinical translation, including inconsistent assessment standards and the lack of non-invasive dynamic monitoring methods. Cutting-edge technological paradigms such as spatial multi-omics, AI-driven computational pathology, and multi-modal liquid biopsy are explored as feasible pathways for precise decoding and standardized assessment of TLSs functional states.</p><p><strong>Results: </strong>Existing evidence highlights the differential impact of iTLSs (favorable outcomes, improved immunotherapy response) versus peritumoral TLSs (dysfunctional or pro-tumorigenic) in HCC. The regulation of TLSs is shown to be deeply intertwined with the liver's unique microenvironment, particularly CAFs and tryptophan metabolism. The analysis points to the potential for integrating advanced technologies to overcome current assessment and monitoring challenges, paving the way for a more precise understanding of TLSs functional states.</p><p><strong>Conclusion: </strong>Addressing the functional paradox of TLSs based on spatial localization in HCC is crucial for guiding treatment. Overcoming current assessment and monitoring bottlenecks through the integration of spatial multi-omics, AI-driven computational pathology, and multi-modal liquid biopsy offers a pathway for precise decoding and standardized evaluation of TLSs functional states. Future research should shift towards active therapeutic interventions targeting TLSs function and location to optimize personalized immunotherapy strategies for HCC patients.</p>","PeriodicalId":13387,"journal":{"name":"Immunological Investigations","volume":" ","pages":"1-38"},"PeriodicalIF":2.4,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-33 in the Regulation of Autophagy and Apoptosis in Macrophages During Infection.","authors":"Ahmet Alperen Palabiyik, Esra Palabiyik","doi":"10.1080/08820139.2025.2547691","DOIUrl":"https://doi.org/10.1080/08820139.2025.2547691","url":null,"abstract":"<p><p><b>Introduction:</b> Interleukin-33 (IL-33) is a multifunctional cytokine from the interleukin-1 family that plays a pivotal role in modulating macrophage responses during infection. Functioning both as an extracellular alarmin and as a nuclear transcriptional regulator, IL-33 orchestrates a dynamic balance between autophagy and apoptosis, crucial for immune homeostasis.<b>Methods:</b> A systematic literature search was conducted in PubMed, Web of Science, and Scopus for studies published between January 2010 and April 2025. Search terms combined \"Interleukin-33\" with keywords related to autophagy, apoptosis, macrophages, and infection.<b>Results:</b> It enhances autophagy by activating AMP-activated protein kinase (AMPK), inhibiting mechanistic target of rapamycin (mTOR), and interacting with Beclin-1 to promote autophagosome formation and LC3 lipidation. Concurrently, IL-33 suppresses apoptosis by upregulating Bcl-2 and Mcl-1, inhibiting Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), and blocking caspase activation. Recent studies also highlight the importance of post-translational modifications (PTMs) and the nuclear domain of IL-33 in fine-tuning these responses. Furthermore, IL-33-based combination therapies with immune checkpoint inhibitors (ICIs) are emerging as promising immunotherapeutic strategies.<b>Discussion:</b> This review synthesizes current insights into IL-33-mediated regulation of macrophage fate and identifies key research gaps. A better understanding of the context-dependent roles of IL-33 will be critical for translating these mechanisms into effective, targeted therapies for infectious and inflammatory diseases.</p>","PeriodicalId":13387,"journal":{"name":"Immunological Investigations","volume":" ","pages":"1-17"},"PeriodicalIF":2.4,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144872964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction Condition Optimization of the M-CSF-Induced Mouse Bone Marrow-Derived Macrophage and the Mechanism Exploration Based on RNA-Seq Analysis.","authors":"Liu Shen, Tingjie Ye, Wei Xu, Fengjun Qiu, Xiaofeng Yan, Hua Li, Xudong Hu","doi":"10.1080/08820139.2025.2542198","DOIUrl":"https://doi.org/10.1080/08820139.2025.2542198","url":null,"abstract":"<p><strong>Background: </strong>Bone marrow-derived macrophage (BMDM) is key tool cell for studying biological processes such as immunity and inflammation. It is also known as a cell drug that can be used for cytotherapy of many diseases such as liver fibrosis. Given the high demand for BMDMs in research, this study explored the most cost-effective, high-productivity method and its molecular mechanism for obtaining Macrophage Colony-Stimulating Factor (M-CSF)-induced mouse BMDM.</p><p><strong>Methods: </strong>A factorial experimental design was employed to examine different induction conditions on BMDM phenotype proportion and productivity, including bone marrow cell (BMC) seeding density, M-CSF concentration, induction time, and removal of bone marrow resident macrophage. Neutral red phagocytosis assay was used to measure phagocytic capacity of BMDM. The mechanism of BMDM proliferation and differentiation was investigated by RNA-seq technology.</p><p><strong>Results: </strong>The most cost-effective and high-productivity BMDM induction protocol is 2 × 10⁵ cells/cm² BMDM seeding density, 80 ng/ml M-CSF induction for 4 days with medium changing once on day 3. BMDM productivity reaches 75.6%. Furthermore, 4-day BMDM showed the strongest phagocytic capacity. RNA-Seq analysis revealed that Cd4, Smad6, Acta2, and Lrrc32 were key target genes regulating BMDM proliferation. Jun, Smad6, Cd4, Fhl2, Hspb1, Id1, and Inhbb were key target genes regulating BMDM differentiation. MAPK, mTOR, TGF-β, and NF-kappa B signaling pathways were the key proliferation or differentiation-related pathways.</p><p><strong>Conclusions: </strong>This study proposes an efficient and economical protocol for BMDM induction. Besides, it explores the regulatory mechanism of M-CSF on BMDM proliferation and differentiation.</p>","PeriodicalId":13387,"journal":{"name":"Immunological Investigations","volume":" ","pages":"1-22"},"PeriodicalIF":2.4,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the Role of <i>Sdc4</i>⁺ Monocytes in NASH: A Single-Cell RNA Sequencing Study.","authors":"Jing-Ze Li, Ting Mao, Yu-Xuan Gao, Ming-Yi Xu, Hui-Yi Li","doi":"10.1080/08820139.2025.2544180","DOIUrl":"https://doi.org/10.1080/08820139.2025.2544180","url":null,"abstract":"<p><strong>Background: </strong>Nonalcoholic steatohepatitis (NASH) involves liver inflammation and fibrosis. Monocytes, key immune cells differentiating into macrophages and dendritic cells, are understudied in NASH using single-cell RNA sequencing (scRNA-seq).</p><p><strong>Methods: </strong>Liver nonparenchymal cells from NASH and control mice underwent scRNA-seq to identify monocyte subsets and transcriptional profiles. Findings were validated via transfection, coculture, immunofluorescence, and qPCR.</p><p><strong>Results: </strong>scRNA-seq analysis revealed that <i>Ly6c</i>^hi monocytes in Cluster 0 appeared to be converted into macrophages in the liver, potentially contributing to the progression of NASH inflammation. Similarly, <i>Ly6c</i>^lo monocytes in Cluster 1 seemed to differentiate into dendritic cells, possibly mediating T-cell immune responses in NASH. Notably, <i>Sdc4</i> was uniquely abundant in Cluster 0. <i>Sdc4</i>⁺ monocytes were elevated in NASH patients and mice versus controls. Under lipotoxic conditions, <i>Sdc4</i>-deficient (sh-<i>Sdc4</i>) monocytes exhibited upregulated expression of <i>CD206</i> (an M2 marker) and <i>IL-10</i>. When cocultured with sh-<i>Sdc4</i> monocytes under palmitic acid stimulation, HepG2 cells accumulated fewer lipid droplets and produced less TNF-α protein, along with increased <i>IL-10</i> genes, compared to controls.</p><p><strong>Conclusion: </strong>Our study elucidates the heterogeneity and functional transformation of two major monocyte subsets in NASH. We foundSdc4+ monocytes may exacerbate NASH through pro-inflammatory mechanisms.</p>","PeriodicalId":13387,"journal":{"name":"Immunological Investigations","volume":" ","pages":"1-16"},"PeriodicalIF":2.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the IL-21/IL-21R Signaling Pathway in Rheumatoid Arthritis: Implications for Synoviocyte Survival and Disease Progression.","authors":"Qiuhua Chen, Shuntao Lin, Sijie Wang, Xiaomei Huang, Liang Liang, Jie Lu, Tong Xie, Xiaoyan Cai","doi":"10.1080/08820139.2025.2542200","DOIUrl":"https://doi.org/10.1080/08820139.2025.2542200","url":null,"abstract":"<p><strong>Introduction: </strong>The persistent presence of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) contributes significantly to joint damage, yet the anti-apoptotic mechanisms involved are not well understood. This study investigates how the interleukin-21 (IL-21)/IL-21 receptor (IL-21R) pathway affects RA-FLS survival during endoplasmic reticulum stress (ERS).</p><p><strong>Methods: </strong>Clinical data, in vitro, and in vivo experiments were comprehensively used.</p><p><strong>Results: </strong>RA patients with moderate-high disease activity and anti-CCP antibodies have high serum IL-21 levels. IL-21 enhances HFLS-RA cell survival and prevents apoptosis under ERS by upregulating IL-21R. It activates autophagy, shown by increased LC3II/I; ratio and p62 degradation, and inhibits ERS-mediated apoptosis by downregulating GRP78 and CHOP. Overexpressing IL-21R boosts autophagy and suppresses ERS. Transcriptome analysis identified USP18 as a key downstream effector of IL-21R. Silencing USP18 increased GSDMD expression and negated IL-21R's protective effects. In vivo, silencing IL-21R reduced joint inflammation and cartilage degradation in RA mouse models, reversing excessive autophagy and ERS marker expression in synovial tissue.</p><p><strong>Discussion: </strong>This study elucidates, for the first time, the mechanism by which IL-21/IL-21R synergistically modulates the survival of RA-FLS through the \"autophagy-ERS balance\" and the USP18/GSDMD axis.</p>","PeriodicalId":13387,"journal":{"name":"Immunological Investigations","volume":" ","pages":"1-24"},"PeriodicalIF":2.4,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}