International immunopharmacology最新文献

{"title":"Cepharanthine protects against lipopolysaccharide-induced acute lung injury in mice by blocking NLRP3 inflammasome activation","authors":"Bingsi Wang ,&nbsp;Longjiao Dang ,&nbsp;Junjie Yang ,&nbsp;Zhizhao Yuan ,&nbsp;Biyao He ,&nbsp;Jiayu Liu ,&nbsp;Ziyi Wang ,&nbsp;Dan Nie ,&nbsp;Lin Gong ,&nbsp;Guige Hou ,&nbsp;Wenyu Xin","doi":"10.1016/j.intimp.2026.116356","DOIUrl":"10.1016/j.intimp.2026.116356","url":null,"abstract":"<div><div>Acute lung injury (ALI) is a common life-threatening lung disease with high mortality and is mostly related to acute inflammatory responses in the lungs. Cepharanthine (CEP), a natural compound extracted from Stefania's genus, has anti-inflammatory and antioxidant properties. However, whether CEP has a protective effect on ALI and its potential mechanism of action are unclear. This study investigated the therapeutic effects and mechanisms of CEP on LPS-induced ALI in mice and related cellular models. CEP alleviated pulmonary inflammation in ALI mice, significantly reducing TNF-α and IL-1β levels in the serum and bronchoalveolar lavage fluid (BALF). CEP inhibited LPS-induced inflammatory responses in MH-S macrophages, as evidenced by reduced proinflammatory cytokine secretion and downregulated NF-κB/NLRP3 signaling. Mechanistically, CEP suppressed the activation of the NF-κB/NLRP3 inflammasome pathway both <em>in vivo</em> and <em>in vitro</em>. Furthermore, CEP attenuated LPS-induced MLE-12 apoptosis, decreasing the expression of apoptosis-related proteins. The protective effects on MLE-12 cells were associated with the inhibition of the NF-κB/NLRP3 pathway. Molecular docking and SPR studies indicated that CEP potentially binds to NLRP3, suggesting a direct interaction. Collectively, these findings demonstrate that CEP mitigates ALI by modulating NF-κB/NLRP3 signaling, suppressing inflammation, and reducing apoptosis, highlighting its potential as a therapeutic candidate for ALI.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116356"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-9 orchestrates immune regulation through CD39/CD73 dependent metabolic reprogramming","authors":"Muhammed Ali Kizmaz,&nbsp;Abdurrahman Simsek,&nbsp;Tugce Bozkurt,&nbsp;Ali Eren Iskin,&nbsp;Ferah Budak","doi":"10.1016/j.intimp.2026.116303","DOIUrl":"10.1016/j.intimp.2026.116303","url":null,"abstract":"<div><div>Adenosine triphosphate (ATP), a principal component of cellular energy metabolism, also functions as a significant extracellular signaling molecule under pathological conditions, including tissue damage and inflammation. The hydrolysis of extracellular ATP (eATP) to adenosine, catalyzed by ectonucleotidases including CD39 and CD73, is a key pathway involved in the control of immune responses. The objective of this study was to systematically examine the capacity of interleukin-9 (IL-9) to regulate ATP–adenosine metabolism and to assess the resultant impact of this regulation on T-cell responses.</div><div>Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were analyzed by flow cytometry (FC) and ELISA to characterize the phenotypic, functional, and metabolic changes induced by IL-9 and to investigate the underlying molecular mechanisms.</div><div>Our findings revealed that while IL-9 did not significantly change the frequency of major T-cell populations, it potentiated the conversion of ATP to adenosine by upregulating the expression of CD39 and CD73. This activity fostered an immunosuppressive microenvironment, especially within regulatory T (Treg) cells. Furthermore, IL-9 treatment suppressed the production of pro-inflammatory cytokines, increased anti-inflammatory cytokine levels, and inhibited T-cell proliferation. The pharmacological inhibition of CD39 and CD73 largely abrogated these IL-9-mediated effects.</div><div>Together, these findings suggest that IL-9 may act as a regulator of the CD39/CD73 axis and that its influence on ATP-adenosine metabolism may have relevance in inflammatory and immune-mediated conditions characterized by dysregulated purinergic signaling.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116303"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RICTOR-mediated GPX4 downregulation regulates chondrocyte ferroptosis in osteoarthritis progression","authors":"Jingting Xu ,&nbsp;Zehang Zheng ,&nbsp;Fei Xin ,&nbsp;Xiong Zhang ,&nbsp;Liangcai Hou ,&nbsp;Wenxin Zhong ,&nbsp;Eryou Feng ,&nbsp;Genchun Wang ,&nbsp;Fengjing Guo","doi":"10.1016/j.intimp.2026.116274","DOIUrl":"10.1016/j.intimp.2026.116274","url":null,"abstract":"<div><div>Osteoarthritis (OA) is the most common degenerative joint disease worldwide and the leading cause of chronic pain and mobility limitation in the elderly. Numerous studies have demonstrated that ferroptosis plays a crucial role in the development and progression of OA; however, the precise mechanisms remain to be elucidated. RICTOR (Rapamycin-Insensitive Companion of mTOR) is a key protein in cellular signal transduction and an essential component of mTORC2 (mammalian target of rapamycin complex 2), vital for the stability and activity of the complex. Our previous work established that RICTOR regulates autophagy to influence OA, yet whether RICTOR affects ferroptosis is unclear. This study aims to investigate the role of RICTOR in chondrocyte ferroptosis and to explore the RICTOR–ferroptosis axis as a potential therapeutic target.First, we observed elevated RICTOR expression in cartilage from OA patients and destabilization of the medial meniscus (DMM) mice, as well as in erastin-treated OA chondrocytes. RICTOR knockdown attenuated erastin-induced reduction of Col2a1 and promoted down-regulation of MMP13. Moreover, the RICTOR inhibitor JR-AB2 ameliorated cartilage degradation in the DMM-induced OA mouse model and mitigated the decline of GPX4 in vivo. Overall, our results indicate that RICTOR induces ferroptosis in OA by regulating GPX4 expression.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116274"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BBB-permeable carbon dots ameliorate Alzheimer's-like phenotypes in mice by suppressing oxidative stress, neuroinflammation, and amyloid-β aggregation","authors":"Ziyue Liu ,&nbsp;Jingmin Wang ,&nbsp;Zifan Chen ,&nbsp;Chongjing Shi ,&nbsp;Zhengquan Tang ,&nbsp;Yongzhong Wang","doi":"10.1016/j.intimp.2026.116298","DOIUrl":"10.1016/j.intimp.2026.116298","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a common neurodegenerative disorder wherein reactive oxygen species (ROS) and Amyloid-β-protein (Aβ) play critical roles. Inspired by traditional Chinese charcoal drug and the anti-inflammatory properties of some carbon dots, we developed <em>Radix Isatidis</em> derived carbon dots (RI-CDs) via a hydrothermal method. The RI-CDs can cross the blood-brain barrier (BBB) and were thus evaluated for AD therapy. In vitro, RI-CDs scavenged ROS, inhibited Aβ₄₂ aggregation, protected SH-SY5Y cells, and regulated inflammatory factors. In AD mice, the Morris water maze test and nesting experiment demonstrated that RI-CDs improved the learning and memory ability of mice and improved their nesting ability. Importantly, RI-CDs reduced ROS/Aβ₄₂ in the hippocampus of AD mice, downregulated NLRP3 pathway-related cellular inflammatory factors, and upregulated the expression of BDNF/SYN/PSD95, thereby restoring damaged neurons. These findings demonstrate the compelling neuroprotective efficacy of RI-CDs, highlighting their potential as a promising therapeutic agent for AD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116298"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM2 regulates neuroinflammation by SYK-dependent inhibition of BTK activation to improve perioperative neurocognitive dysfunction","authors":"Kaiyun Zhang ,&nbsp;Wenying Chi ,&nbsp;Junzuo Guo ,&nbsp;Yaru Huang ,&nbsp;Zhe Zhang ,&nbsp;Xinlei Guo ,&nbsp;Bowen Zhang ,&nbsp;Fanjun Meng","doi":"10.1016/j.intimp.2026.116269","DOIUrl":"10.1016/j.intimp.2026.116269","url":null,"abstract":"<div><div>This study investigates the role of the TREM2-SYK-BTK signaling pathway in microglial activation and cognitive decline. In vivo and in vitro experiments demonstrate that surgical trauma induces BTK phosphorylation in hippocampal microglia, promoting their transition towards a pro-inflammatory M1 phenotype while suppressing the anti-inflammatory M2 phenotype. In a perioperative neurocognitive disorder (PND) mouse model, hippocampal injection of AAV-BTK siRNA suppressed BTK phosphorylation, promoting microglial transition from M1 to M2 phenotype. This shift manifested as reduced pro-inflammatory cytokines (IL-1β, IL-6) and increased anti-inflammatory cytokines (IL-4, IL-10), ultimately alleviating cognitive impairment. Further mechanistic analysis revealed that TREM2 regulates microglial inflammatory balance by enhancing SYK phosphorylation to inhibit BTK activity, an effect antagonized by the SYK inhibitor R406. Subsequent studies indicate this pathway modulates neuroinflammation by regulating NF-κB signaling and NLRP3 inflammasome activation. These findings illustrate that TREM2-SYK-BTK signaling pathway is the key internal mechanism to regulate microglial polarization and neuroinflammation, which provides a new theoretical basis and potential therapeutic strategy for PND.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116269"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146062753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinoic acid receptor gamma (RARγ) drives M2-like macrophage polarisation via CFI to promote thyroid cancer progression","authors":"Jiahuang Liu ,&nbsp;Zhangquan Yang ,&nbsp;Fahui Liu ,&nbsp;Shihang Tang ,&nbsp;Xuesi Yang ,&nbsp;Hongliang Zhan ,&nbsp;Dongyan Shen ,&nbsp;Fuxing Zhang","doi":"10.1016/j.intimp.2026.116324","DOIUrl":"10.1016/j.intimp.2026.116324","url":null,"abstract":"<div><div>Thyroid carcinoma (TC), the most prevalent endocrine malignancy, accounts for 3–4% of global cancer cases and continues to increase in incidence worldwide. Despite advances in diagnosis and treatment, a subset of thyroid cancers remains clinically incurable, underscoring the urgent need to elucidate molecular pathogenesis and identify novel therapeutic targets. Here, we identify complement factor I (CFI) as a key downstream effector of Retinoic acid receptor gamma (RARγ). Mechanistically, RARγ transcriptionally upregulates CFI expression, and analyses of clinical TC specimens demonstrated a strong correlation between RARγ and CFI expression. Conditioned media from RARγ-overexpressing TC cells induced M2-like polarisation of THP-1–derived macrophage-like cells, as evidenced by increased CD206 expression and elevated IL-10 levels—effects that were abolished by CFI neutralisation. In xenograft models, RARγ/CFI-mediated TAM reprogramming drove tumour progression, with RARγ-knockdown tumours exhibiting reduced volumes via macrophage-dependent mechanisms. Importantly, CFI did not affect TC cell-autonomous proliferation, suggesting that its pro-tumoural effects are mediated by the TME rather than directly on tumour cells. Collectively, Our findings establish RARγ/CFI signalling as a microenvironmental rheostat controlling TAM polarisation and provide new insights into the immunobiology of thyroid cancers.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116324"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 E protein reduces PPARA activity in colonic and pulmonary epithelial cells, driving diarrhea and pneumonia in COVID-19","authors":"Qiuyue Wu ,&nbsp;Mengyuan Zhou ,&nbsp;Xiaoyue Feng ,&nbsp;Yi Shen ,&nbsp;Weijun Jiang ,&nbsp;Xueyan Liu ,&nbsp;Zhenyu Liu ,&nbsp;Min Chen ,&nbsp;Jing Zhang ,&nbsp;Fangyu Wang ,&nbsp;Xiaodong Song ,&nbsp;Weijun Xu ,&nbsp;Hongjian Zhou ,&nbsp;Xinyi Xia","doi":"10.1016/j.intimp.2026.116291","DOIUrl":"10.1016/j.intimp.2026.116291","url":null,"abstract":"<div><div>Although diarrhea is common in COVID-19, its underlying mechanisms remain unclear. Using clinical data from 3023 patients and single-cell RNA sequencing of colonic tissues, we found that diarrhea was associated with higher disease severity and mortality. scRNA-seq (<em>n</em> = 1 COVID-19 patient with diarrhea) of colonic tissue from deceased patient, and experimental validation to elucidate the mechanisms of SARS-CoV-2–induced diarrhea and identify potential therapeutic targets. Clinical analysis revealed that diarrhea was associated with more severe disease and higher mortality rates. scRNA-seq identified significant downregulation of membrane transporters (SLC9A3, SLC26A3, and SPINT2) in colonic epithelial cells of colonic tissue from one deceased COVID-19 patient. Gene regulon network analysis pinpointed PPARA as a master regulator of these proteins, with its activity suppressed post-infection. Further experiments confirmed that E protein stimulation reduced PPARA activity and the expression of membrane transporters, leading to a diarrheal phenotype (OR = 3.33 for diarrhea as risk factor) in vitro cell culture models. Interestingly, we found PPARA activity was also decreased in SARS-CoV-2–infected lung epithelial cells, where it regulated CFTR expression, contributing to pneumonia. Treatment with PPARA agonists rescued the expression of these proteins, mitigating both diarrheal and pneumonia phenotypes. Our findings reveal a common mechanism by which the SARS-CoV-2 E protein inhibits PPARA activity in both colonic and lung epithelial cells, leading to severe clinical outcomes. PPARA agonists may represent a novel therapeutic strategy for COVID-19–associated diarrhea and pneumonia in vitro cell culture models.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116291"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BDNF and NLRP3 signaling differentially regulate formation and retrieval of nitrous oxide (N2O)-related rewarding memory in dorsal hippocampus CA3 region","authors":"Huarong Shen ,&nbsp;Yatong Shi ,&nbsp;Jiancheng Xu ,&nbsp;Yuxu Ren ,&nbsp;Xiaoyu Xia ,&nbsp;Tianyi Zang ,&nbsp;Yi-Feng Cheng ,&nbsp;Junlong Zhang ,&nbsp;Tengfei Ma ,&nbsp;Fangyuan Yin","doi":"10.1016/j.intimp.2026.116327","DOIUrl":"10.1016/j.intimp.2026.116327","url":null,"abstract":"<div><div>The formation and retrieval of reward memories within the hippocampus are critical mechanisms underlying the development of substance use disorder. Nitrous oxide (N₂O), an inhalant with significant abuse potential, is believed to hijack these processes, yet the precise hippocampal mechanisms remain unknown. Here, we reported that N₂O-related memory stages are differentially regulated by BDNF and NLRP3 signaling in the dorsal hippocampus CA3 region. First, we found that N₂O exposure induces conditioned place preference (CPP) and preferentially increases the activity of hippocampal CA3 neurons. Furthermore, N₂O concurrently enhances both the BDNF expression and the microglia activity in hippocampal CA3 region. The mechanisms are involved in activation of both BDNF-TrkB-pAKT and the microglia-NLRP3 signaling pathways. Interestingly, knockdown of BDNF expression in the CA3 region reduces retrieval, but not formation stage, of CPP behavior. Whole-cell patch-clamp recordings further demonstrated that CA3-specific BDNF knockdown abolishes the N₂O-induced potentiation of glutamatergic transmission. Finally, both pharmacological microglial inhibition and germline NLRP3 deletion prevented the N₂O-induced formation stage of CPP behavior. Our study elucidates a novel, stage-specific regulatory mechanism in which BDNF-TrkB-pAKT and the microglia-NLRP3 signaling within the hippocampal CA3 differentially governs the retrieval versus formation of N₂O reward memory, revealing distinct targets for therapeutic intervention.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116327"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of vildagliptin-induced liver injury: An idiosyncratic drug reaction mediated by inflammasome activation","authors":"Serina Mizuguchi ,&nbsp;Saori Tanaka ,&nbsp;Rei Aoki ,&nbsp;Takumi Noda ,&nbsp;Kazuya Urashima ,&nbsp;Ayumi Fujimoto ,&nbsp;Mayuko Takaori-Tamura ,&nbsp;Ayaka Kidani ,&nbsp;Jina Suzuki ,&nbsp;Yuka Kohda ,&nbsp;Ryuji Kato","doi":"10.1016/j.intimp.2026.116301","DOIUrl":"10.1016/j.intimp.2026.116301","url":null,"abstract":"<div><div>Vildagliptin has been reported to cause liver injury, with clinical findings suggesting the involvement of the immune response. However, the underlying mechanism remains unclear. Vildagliptin possesses a covalent-binding group that may induce an immune response <em>via</em> inflammasome activation. In this study, we examined whether covalent binding of vildagliptin to proteins in differentiated THP-1 or FLC-4 cells leads to inflammasome activation either directly or <em>via</em> damage-associated molecular patterns (DAMPs). We also performed biochemical and histopathological assessments of liver injury in PD-1^−/− mice treated with anti-CTLA-4 antibody and vildagliptin (0.13%). Vildagliptin didn't directly induce IL-1β production and Caspase-1 activity in differentiated THP-1 cells. In contrast, the culture medium of FLC-4 cells incubated with vildagliptin exhibited increased levels. The levels of heat shock protein 40 (HSP40), a DAMP that triggers inflammasome activation, were significantly increased in the culture supernatant. In addition, adducts with a trapping agent were detected in FLC-4 cells, suggesting that covalent binding of vildagliptin induces the release of DAMPs. In mice with impaired immune tolerance due to immune checkpoint blockade, serum AST and ALT levels were significantly elevated 4 weeks after treatment with vildagliptin, and marked granulomatous inflammation was observed in the liver tissues. These results indicate that vildagliptin-induced liver injury occurs <em>via</em> a mechanism whereby the covalent binding of vildagliptin induces the release of HSP40 from hepatocytes, in turn activating inflammasomes. We further demonstrated that the risk of vildagliptin-induced liver injury may be increased by impaired immune tolerance, such as that caused by the co-administration of immune checkpoint inhibitors.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116301"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblast-derived CCL2 driven by MIF promotes joint capsule fibrosis via macrophage polarization regulation","authors":"Yuxin Zhang ,&nbsp;Jiling Ye ,&nbsp;Yuxiang He ,&nbsp;Yijia Wang ,&nbsp;Minghui Lin ,&nbsp;Zhigang Wu","doi":"10.1016/j.intimp.2026.116319","DOIUrl":"10.1016/j.intimp.2026.116319","url":null,"abstract":"<div><div>Post-traumatic joint contracture (PTJC) is driven by persistent joint capsule inflammation and subsequent fibrosis. C<img>C motif chemokine ligand 2 (CCL2) is recognized as a key regulator of sustained inflammation. However, the relevant regulatory mechanism involved in CCL2 production in PTJC has not been fully elucidated. In this study, we investigated whether MIF can facilitate CCL2 production from fibroblasts and regulate joint capsule fibrosis following PTJC. Our data demonstrated that PTJC-induced elevation of CCL2 levels was synchronous with MIF. Administration of MIF inhibitor 4-IPP at the lesion sites significantly reduced the expression of CCL2. An in vitro study revealed that MIF potently facilitated the production of CCL2 in joint capsule fibroblasts through interaction with CD74 receptor and subsequent activation of JNK/CREB signaling. Interestingly, fibroblast-derived CCL2 promoted macrophage excessive polarization toward M2 phenotype through the C<img>C motif chemokine receptor 2 (CCR2), thereby amplifying chronic inflammation and fibrosis. The inhibition of MIF activity prevented the pro-fibrotic process by decreasing CCL2. Our results provide insights into the new functions of MIF-mediated CCL2 production in fibroblasts, which exacerbates the pathological microenvironment by tuning joint capsule inflammation and fibrosis during PTJC. The present study may provide a new therapeutic strategy for other inflammation- and fibrosis-associated diseases.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116319"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}