International immunopharmacology最新文献

{"title":"Hedyotis diffusa injection modulates the ferroptosis in bladder cancer via CAV1/JUN/VEGFA","authors":"Kaiping Bai ,&nbsp;Yanxi Long ,&nbsp;Fei Yuan ,&nbsp;Xiaoling Huang ,&nbsp;Pengtao Liu ,&nbsp;Yanping Hou ,&nbsp;Xiangyu Zou ,&nbsp;Tao Jiang ,&nbsp;Jie Sun","doi":"10.1016/j.intimp.2024.113925","DOIUrl":"10.1016/j.intimp.2024.113925","url":null,"abstract":"<div><div>Hedyotis diffusa Willd. (HDW), a traditional Chinese medicinal plant, exhibits a variety of pharmacological effects and has anticancer potential for a wide range of cancer types; Ferroptosis is a non-apoptosis-regulated cell death induced by iron accumulation and subsequent lipid peroxidation; and there is currently an increasing interest in the therapeutic role of ferroptosis in cancer. However, the effects of HDW on bladder cancer and its underlying molecular mechanisms remain largely unknown. In this study, a combination of in vivo and in vitro experiments, network pharmacology and data mining methods were used to investigate the effects of HDW on BLCA. The results showed that HDW exerted its anticancer activity by inducing ferroptosis in bladder cancer cells. Subsequently, we demonstrated for the first time that HDW induced ferroptosis in vitro and in vivo. To further explore the possible targets of HDW-induced ferroptosis in bladder cancer, we performed network pharmacological analyses, transcriptomic analyses, and single-cell analyses; through integrative analyses, we identified three key pivotal genes associated with iron death, CAV1, VEGFA, and JUN.Mechanistically, we showed that CAV1, VEGFA and JUN are key determinants of HDW-induced ferroptosis in BLCA. Knockdown of target genes altered the anticancer effects of HDW in 5637 and T24 cells. In conclusion, our data show for the first time that HDW exerts its anticancer effects on BLCA through CAV1, VEGFA and JUN gene-induced ferroptosis. This is expected to provide a promising compound for bladder cancer therapy.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113925"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052232","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":"3,6-Anhydro-L-galactose suppresses mouse lymphocyte proliferation by attenuating JAK-STAT growth factor signal transduction and G1-S cell cycle progression","authors":"Shin Young Park ,&nbsp;Ki Yun Kim ,&nbsp;Won Young Jang ,&nbsp;Young-Seuk Bae ,&nbsp;Do Youn Jun ,&nbsp;Young Ho Kim","doi":"10.1016/j.intimp.2024.113998","DOIUrl":"10.1016/j.intimp.2024.113998","url":null,"abstract":"<div><div>Recombinant GH16B β-agarase-catalyzed liquefaction of 5–7 %(w/v) melted agarose at 50 °C completely hydrolyzed agarose into neoagarohexaose (NA6) and neoagarotetraose (NA4). Subsequent saccharification by recombinant GH50A β-agarase or recombinant GH50A β-agarase/recombinant GH117A α-neoagarobiose hydrolase at 35 °C converted NA6/NA4 into neoagarobiose (NA2) or 3,6-anhydro-L-galactose (L-AHG)/D-galactose, respectively. Purification of NA6/NA4 and NA2 was achieved by Sephadex G-15 column chromatography, while L-AHG was purified by Sephadex G-10, achieving ≥ 98 % purity. L-AHG (25–200 μg/mL), but not NA2, NA4, or NA6, inhibited the proliferation of immobilized anti-CD3/anti-CD28-activated T cells and immobilized anti-CD40 + soluble anti-IgM + interleukin (IL)-4-activated B cells. This inhibition impacted the G₁-S traverse in the cell cycle without influencing CD69 expression and p27^Kip1 down-regulation, markers of the exit from G₀ into G₁ phase in activated lymphocytes. L-AHG impeded cyclin-dependent kinases (CDKs)-driven retinoblastoma phosphorylation, necessary for the G₁-S traverse, by reducing the activating phosphorylation of CDKs (CDK4, CDK2, and CDK1) and lowering cyclin D3, cyclin A2 and cyclin B1 levels. Furthermore, L-AHG diminished the production of growth factors, including IL-2 in activated T cells and IL-6 in activated B cells. The antiproliferative effect of L-AHG on T cells was partially restored by exogenous IL-2 but was unaffected by exogenous IL-6 on B cells. L-AHG inhibited the activating phosphorylation of Janus kinase 1 (JAK1), affecting signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling. These results demonstrate that L-AHG may serve as a novel immunosuppressant by impairing JAK-STAT growth factor signaling and G₁-S cell cycle progression in T and B lymphocytes.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113998"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Betulin inhibits the production of inflammatory cytokines in human gingival fibroblasts and ligature-induced periodontitis","authors":"Ya-Hsin Wu ,&nbsp;Fátima Daniela Marroquín Ramírez ,&nbsp;Yen-You Lin ,&nbsp;Tzong-Ming Shieh ,&nbsp;Tzu-Ching Chang ,&nbsp;Chih-Hsin Tang","doi":"10.1016/j.intimp.2025.114018","DOIUrl":"10.1016/j.intimp.2025.114018","url":null,"abstract":"<div><div>Chronic inflammation of the tissues surrounding and supporting the teeth is known as periodontal disease. Human gingival fibroblasts (HGFs) are among the greatest prevalent cells in gingival tissue and play a crucial role in oral infections. Data from the GSE dataset revealed that the inflammatory cytokines IL-1β, IL-6, and IL-8 were up-regulated in periodontitis patients compared to healthy individuals. Betulin, a lupane-type pentacyclic triterpene alcohol extracted from the birch trees, inhibits lipopolysaccharide (LPS; component of gram-negative bacteria)-induced synthesis of IL-1β, IL-6, and IL-8 in HGFs. We also demonstrated that the MAPK and AP-1 signaling cascades mediate betulin’s inhibition of inflammatory cytokine production in HGFs. Importantly, betulin reduces the expression of inflammatory cytokines and prevents the progression of ligature-induced periodontitis <em>in vivo</em>. This study provides evidence that betulin is a promising candidate for the management of periodontal disease.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114018"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055941","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":"Unveiling the role of ACTL6A in uveal melanoma metastasis and immune microenvironment","authors":"Liu Weiqin ,&nbsp;Wan Qi ,&nbsp;Jin Lin ,&nbsp;Chen Shuxia ,&nbsp;Liu Chang","doi":"10.1016/j.intimp.2024.113841","DOIUrl":"10.1016/j.intimp.2024.113841","url":null,"abstract":"<div><h3>Purpose</h3><div>To predict and evaluate the possible mechanisms and clinical value of <em>ACTL6A</em> in the prognosis and development of UM.</div></div><div><h3>Methods</h3><div>Bioinformatics analyze the relationship between <em>ACTL6A</em> and immunity in UM, which derived from TCGA, Gene Expression Omnibus (GEO) databases. Tumor-infltrated immune cells were demonstrated using QUANTISEQ and MCP-counter. Furthermore, scRNA-seq was used to detect <em>ACTL6A</em> expression, distribution, immune infiltration and revealing the gene expression profile of UM.</div></div><div><h3>Results</h3><div>The expression of <em>ACTL6A</em> was lower in UM compared with pantumor in TCGA databases. Kaplan-Meier analysis revealed that downregulated <em>ACTL6A</em> was associated with poor OS, and <em>ACTL6A</em> was associated with cancer stem cells (CSCs) and immune infiltration. Moreover, <em>ACTL6A</em> might act as a chemotherapy resistance gene and closely relate- to epithelial-mesenchymal transition. Analysis in 8 GSE databases showed that <em>IL13, TPTE, IL17B</em> and <em>CCL22</em> genes were significantly overexpressed in metastatic UM. Furthermore, the single-cell transcriptomic profling identified a new cell cluster - as a unique type of immune cell, which associating with malignant cell heterogeneity and complexity, and further revealing that the metastasis of UM is mainly associated with CD4 Tconv, B , CD8 Tex, and Plasma cells.</div></div><div><h3>Conclusions</h3><div>Downregulated ACTL6A acts as a risk factor for poor prognosis in UM, which implies as an potential prognostic marker for independent targeted immunotherapy.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113841"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921693","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":"HMGB1 induces unexplained recurrent spontaneous abortion by mediating decidual macrophage autophagy","authors":"Xingxing Han ,&nbsp;Yu Ren ,&nbsp;Xueke Zhang ,&nbsp;Damin Zhu ,&nbsp;Zihan Meng ,&nbsp;Qiqi Zhang ,&nbsp;Beili Chen ,&nbsp;Ping Zhou ,&nbsp;Zhaolian Wei ,&nbsp;Yunxia Cao ,&nbsp;Xiaofeng Xu ,&nbsp;Zhiguo Zhang ,&nbsp;Huijuan Zou","doi":"10.1016/j.intimp.2024.113999","DOIUrl":"10.1016/j.intimp.2024.113999","url":null,"abstract":"<div><h3>Background</h3><div>The overexpression of HMGB1 at the maternal-fetal interface (MFI) is recognized as a significant factor in Unexplained Recurrent Spontaneous Abortion (URSA). This study aimed to investigate autophagy in the decidual tissues of URSA patients and to explore the relationship between HMGB1 and macrophage autophagy at the MFI in URSA.</div></div><div><h3>Methods</h3><div>Human decidual tissues were collected from 40 patients diagnosed with URSA and from 60 women undergoing active termination of pregnancy. Mouse models of pregnancy loss URSA and in vitro cellular models were created and then subjected to treatment with an HMGB1 inhibitor (aspirin) and an anti-HMGB1 antibody, respectively. Autophagy at the MFI was evaluated using western blot analysis, immunofluorescence assays, and transmission electron microscopy (TEM).</div></div><div><h3>Results</h3><div>This study revealed a high expression of LC3B and a low expression of P62 in the decidual tissue of the URSA group. These findings were further corroborated through TEM. The localization of autophagy within macrophages indicated a significant enhancement of autophagy in the decidual macrophages of the URSA group. However, treatment with low-dose aspirin resulted in a reversal of protein expression and a reduction in autophagy. In in vitro experiments, recombinant HMGB1 was found to mediate autophagy of immortalized bone marrow-derived macrophages, which could be inhibited by an anti-HMGB1 antibody.</div></div><div><h3>Conclusion</h3><div>This study first indicates that elevated levels of HMGB1 at the MFI trigger autophagy in macrophages, thereby promoting aseptic inflammation and contributing to the onset and progression of URSA. Furthermore, low-dose aspirin has been demonstrated to protect against URSA by inhibiting HMGB1, which in turn suppresses autophagy production.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113999"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948301","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":"Application of cell therapy in rheumatoid Arthritis: Focusing on the immunomodulatory strategies of Mesenchymal stem cells","authors":"Zhi Feng ,&nbsp;Ying Yang ,&nbsp;Xiang-zhuo Liu ,&nbsp;Hui-jiao Sun ,&nbsp;Bo-ya Wen ,&nbsp;Zhi Chen ,&nbsp;Bo Wei","doi":"10.1016/j.intimp.2025.114017","DOIUrl":"10.1016/j.intimp.2025.114017","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a common chronic autoimmune disease that primarily affects the joints, leading to synovial inflammation and hyperplasia, which subsequently causes joint pain, swelling, and damage. The microenvironment of RA is characterized by hypoxia, high reactive oxygen species (ROS), low pH, and levels of high inflammatory factors. Traditional treatments only partially alleviate symptoms and often cause various adverse reactions with long-term use. Therefore, there is an urgent need for safer and more effective treatments. In recent years, mesenchymal stem cells (MSCs) have shown significant potential in treating RA due to their diverse immunomodulatory mechanisms. MSCs paracrine a variety of soluble factors to improve the inflammatory microenvironment in RA patients by inhibiting T cell proliferation or inducing T cell differentiation to regulatory T cells (Tregs), inhibiting B cell proliferation and differentiation and immunoglobulin production, prompting macrophage polarization toward an anti-inflammatory phenotype, and inhibiting neutrophil recruitment and preventing the maturation of dendritic cells (DCs). This review summarizes the immunomodulatory effects of MSCs in RA and their application in animal models and clinical trials. Although the immunomodulatory mechanisms of MSCs are not yet fully elucidated, their significant potential in RA treatment has been widely recognized. Future research should further explore the immunomodulatory mechanisms of MSCs and optimize their functions in different pathological microenvironments to develop more effective and safer therapeutic strategies.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114017"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948483","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":"Association of sulfur mustard toxicity with oxidant/antioxidant system in veterans: A meta-analysis of case-control studies","authors":"Hossein Hassanpour ,&nbsp;Marzieh Mojtahed ,&nbsp;Leila Nasiri ,&nbsp;Mohammad-Reza Vaez-Mahdavi ,&nbsp;Aziz A. Fallah","doi":"10.1016/j.intimp.2024.114007","DOIUrl":"10.1016/j.intimp.2024.114007","url":null,"abstract":"<div><div>Sulfur mustard (SM) is a chemical warfare agent that increases oxidative stress in veterans. The literature assessing oxidant/antioxidant parameters in SM-exposed veterans contains conflicting results. A total of 11 relevant studies were identified and screened. Data were extracted, and effect size and heterogeneity were assessed. The analysis revealed significant elevations in levels of malondialdehyde (MDA, an indicator of lipid peroxidation), catalase (CAT), and a reduction in glutathione (GSH) following SM exposure while superoxide dismutase (SOD) and total antioxidant levels did not change. The <em>meta</em>-analysis revealed that the MDA and CAT levels significantly increased in the two post-exposure sampling times (15–20 and 21–33 years) except for the<!--> <!-->GSH level, which decreased only in the post-exposure sampling time of 21–33 years. The subgroup <em>meta</em>-analysis of the type of analyzed samples indicated that SOD and CAT levels were only increased in the serum/plasma samples, while GSH was decreased. BALF/sputum and erythrocyte samples also revealed significant increases in MDA and SOD levels while GSH level was significantly decreased. This <em>meta</em>-analysis concluded that SM exposure affects the balance between oxidants and antioxidants, promoting oxidative stress that may persist long after exposure. This condition highlights the need for strategies to enhance antioxidant defenses in SM-exposed veterans.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114007"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964529","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":"Microglial HO-1 aggravates neuronal ferroptosis via regulating iron metabolism and inflammation in the early stage after intracerebral hemorrhage","authors":"Qi Liu ,&nbsp;Ziyi Han ,&nbsp;Tao Li ,&nbsp;Jincheng Meng ,&nbsp;Chenwei Zhu ,&nbsp;Junmin Wang ,&nbsp;Jian Wang ,&nbsp;Zhen Zhang ,&nbsp;He Wu","doi":"10.1016/j.intimp.2024.113942","DOIUrl":"10.1016/j.intimp.2024.113942","url":null,"abstract":"<div><div>Heme oxygenase 1 (HO-1), an enzyme involved in heme catabolism, has been shown upregulated in microglia cells and plays a critical roles in neurological damages after intracerebral hemorrhage (ICH). However, the mechanisms by which HO-1 mediates the neuronal damages are still obscure. Here, our findings demonstrate that HO-1 over-expression exacerbates the pro-inflammatory response of microglia and induces neuronal ferroptosis through promoting intracellular iron deposition in the ICH model both in vitro and in vivo. Furthermore, in the co-cultured ICH model in vitro, we verify that HO-1 over-expression disrupts the balance of iron metabolism in microglia, which increases the iron efflux to the extracellular space and promotes iron ion uptake in neurons, leading to lipid peroxidation injury and further contributing to neuronal ferroptosis. Moreover, the specific ferroptosis inhibitor Ferrostatin-1 (Fer-1) treatment could mitigate the damages in the co-cultured HT22 cells that caused by HO-1 over-expression in microglia, and improve the neurological function in the ICH model in mice. By shedding light on the mechanisms of aggravating neuronal ferroptosis due to HO-1 overexpression in the early stages after ICH, our study provides insights into the potential therapy of targeting HO-1 to treat ICH.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113942"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repressing cytokine storm-like response in macrophages by targeting the eIF2α-integrated stress response pathway","authors":"Xiaoyun Wang ,&nbsp;Chaochao Dai ,&nbsp;Wen Cheng ,&nbsp;Jianli Wang ,&nbsp;Xiaopei Cui ,&nbsp;Guopin Pan ,&nbsp;Ye Chen ,&nbsp;Yu Han ,&nbsp;Xiaosun Guo ,&nbsp;Fan Jiang","doi":"10.1016/j.intimp.2024.113965","DOIUrl":"10.1016/j.intimp.2024.113965","url":null,"abstract":"<div><div>Cytokine storm is a life-threatening systemic hyper-inflammatory state caused by different etiologies, in which the bulk production of pro-inflammatory cytokines from activated macrophages has a central role. Integrated stress response (ISR) comprises several protective signaling pathways, leading to phosphorylation of eukaryotic initiation factor 2α (eIF2α) and repression of protein translation. Emerging evidence suggests that ISR induction may elicit anti-inflammatory effects. Currently, however, it is unclear whether targeting eIF2α phosphorylation is sufficient to inhibit the cytokine storm-like response in macrophages. Here we carried out a proof-of-concept study, employing two approaches: (1) ectopic expression of the eIF2α-S51D mutant (mimicking the phosphorylated eIF2α); (2) treatment with salubrinal, a small molecule inhibitor of eIF2α dephosphorylation. Experiments were performed in lipopolysaccharides (LPS)-stimulated macrophages and in murine models with LPS-induced acute endotoxemia. We demonstrated that in macrophages, ectopic expression of eIF2α-S51D, treatment with salubrinal, and gene silencing of PP1/GADD34 (the phosphatase holoenzyme mediating eIF2α dephosphorylation) significantly inhibited LPS-induced cytokine productions without changing their mRNA levels. Polysome PCR and puromycin incorporation assays confirmed that salubrinal suppressed <em>de novo</em> protein translation of the cytokines. <em>In vivo,</em> salubrinal pre-treatment mitigated LPS-induced acute lung injury and significantly reduced the concentration of circulating TNF-α. Salubrinal did not exhibit any effects on the Toll-like receptor 4-mediated signaling or the activation of mammalian target of rapamycin (mTOR). Our data suggest that direct manipulation of eIF2α phosphorylation, thereby bypassing all associated upstream signaling events, may suppress the cytokine storm-like response in activated macrophages, likely by decoupling the gene transcription and protein translation. Inhibiting eIF2α dephosphorylation with small molecule inhibitors may be a viable therapeutic strategy to treat disorders involving cytokine storm-like responses.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113965"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927238","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":"SLC7A11 suppresses pyroptosis to alleviate rheumatoid arthritis development by modulating the IL-17 pathway","authors":"Shaojian Chen ,&nbsp;Longqiang Zou ,&nbsp;Liangcai Huang ,&nbsp;Zhengnan Li ,&nbsp;Hui Zeng ,&nbsp;Yanmei Zeng ,&nbsp;Juan Wu","doi":"10.1016/j.intimp.2025.114019","DOIUrl":"10.1016/j.intimp.2025.114019","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. This study aims to explore the potential mechanisms by which solute carrier family 7 member 11 (<em>SLC7A11</em>) influences RA development.</div></div><div><h3>Methods</h3><div>Collagen-induced arthritis (CIA) mice were constructed to observe disease onset and pathological scores. Pathological changes were examined using Hematoxylin-eosin and Safranin O-Fast Green staining. Levels of lactate dehydrogenase (LDH), inflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-18 and IL-1β), and oxidative stress (reactive oxygen species, malondialdehyde, and glutathione) were measured using ELISA. Western blotting was performed to detect the expression of pyroptosis- and pathway-related proteins. Fibroblast-like synoviocytes of RA (RA-FLS) were treated with TNF-α. Cell migration, invasion, and Caspase-1 levels were assessed through scratch assays, Transwell assays, and flow cytometry, respectively. The correlation between <em>SLC7A11</em> and immune cell infiltration in RA was analyzed using bioinformatics. Additionally, downstream pathways of <em>SLC7A11</em> in RA were screened, and the impacts of <em>SLC7A11</em> on these pathways were validated <em>in vitro</em>.</div></div><div><h3>Results</h3><div>CIA mice were successfully established, revealing significant downregulation of <em>SLC7A11</em> in RA. Staining results indicated that overexpression of <em>SLC7A11</em> significantly mitigated joint damage in CIA mice. <em>In vitro</em> experiments demonstrated that overexpression of <em>SLC7A11</em> inhibited migration, invasion, and Caspase-1 expression levels in TNF-α-induced RA-FLSs. Furthermore, <em>SLC7A11</em> suppressed inflammation, LDH release, and oxidative stress, while inhibiting pyroptosis. <em>SLC7A11</em> expression was significantly different in multiple immune cells. The <em>IL-17</em> pathway was identified as a downstream pathway of <em>SLC7A11</em>, and <em>SLC7A11</em> inhibited the expression of <em>IL-17</em> pathway proteins. Additionally, rhIL-17A, an activator of the <em>IL-17</em> pathway, attenuated the inhibitory effects of <em>SLC7A11</em> on inflammation, oxidative stress, and pyroptosis.</div></div><div><h3>Conclusion</h3><div><em>SLC7A11</em> suppresses pyroptosis to alleviate RA development by inhibiting the <em>IL-17</em> pathway.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114019"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970599","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}