Yujiao Chen , Min Chen , Huifang Chen , Jin-hong Zhu , Chanyang Liang , Sijie Wu , Suda Gu , Weimin Sun , Jie Yan
{"title":"Crosstalk patterns of necroptosis signaling and NLRP3 inflammasome in the colonic epithelium and its initial role in colitis","authors":"Yujiao Chen , Min Chen , Huifang Chen , Jin-hong Zhu , Chanyang Liang , Sijie Wu , Suda Gu , Weimin Sun , Jie Yan","doi":"10.1016/j.intimp.2025.114413","DOIUrl":"10.1016/j.intimp.2025.114413","url":null,"abstract":"<div><div>Inflammation-mediated epithelial damage, including necroptosis of the intestinal epithelia, can lead to subsequent immune responses, but the molecular mechanisms of inflammation in the initial stages are not well understood. Based on cellular experiments and mouse models, we investigated the activation of the NLRP3 inflammasome under necroptotic conditions, and its contribution to the inflammatory response in colitis. Our results showed that, under inflammatory conditions, intestinal epithelial cells (IECs) undergo phosphor-MLKL-dependent necroptosis with subsequent activation of the NLRP3 inflammasome for caspase-1 activation and IL-1β maturation. Mechanisms investigation revealed that components of the inflammasome were primed through the NF-κB signaling pathway and ASC-NLRP3 organization was dependent on mitochondrial reactive oxygen species (ROS), which could be promoted by necroptosis signaling. In addition, we found that Tempol, a kind of compound for ROS neutralization, could effectively reduce intestinal inflammation in mice by inhibiting the activation of the NLRP3 pathway in epithelia. Taken together, our research suggests that the necroptosis-triggered NLRP3 inflammasome in IECs plays an important role in the initiation of epithelial shedding and further inflammatory response in colitis. Our results provide a novel insight into the use of the ROS inhibitor Tempol as a treatment for the prevention of immune response and inflammation-induced tissue damage in the intestinal epithelium and thus as a potential therapeutic target for IBD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114413"},"PeriodicalIF":4.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620313","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}
Bingyu Li , Shanlong Wang , Xiaohui Li , Ping Wang , Dan Ii , Longchao Ran , Jufeng Li , Rongzeng Liu , Sanqiang Li , Lijun Xu
{"title":"Macrophage-targeting combination therapy enhances T-DXd-induced tumor regression","authors":"Bingyu Li , Shanlong Wang , Xiaohui Li , Ping Wang , Dan Ii , Longchao Ran , Jufeng Li , Rongzeng Liu , Sanqiang Li , Lijun Xu","doi":"10.1016/j.intimp.2025.114378","DOIUrl":"10.1016/j.intimp.2025.114378","url":null,"abstract":"<div><div>Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic approach for HER2-positive cancers, with trastuzumab deruxtecan (T-DXd) demonstrating significant efficacy. However, resistance mechanisms often limit the effectiveness of ADC monotherapy. This study explores the potential of combining T-DXd with macrophage-targeting therapies, specifically anti-SIRPα antibodies and PI3Kγ inhibitors, to enhance anti-tumor immunity. Utilizing HER2-positive preclinical models, we hypothesized that this triple combination would synergistically promote immunogenic cell death (ICD) and reprogram tumor-associated macrophages (TAMs). Our results demonstrated that the combination of T-DXd, anti-SIRPα, and IPI-549 significantly inhibited tumor growth compared to monotherapies, with no major weight loss, indicating a favorable tolerability profile. Sequential treatment further enhanced tumor control, achieving complete regression in some cases. Importantly, previously treated mice developed durable immunological memory, completely rejecting subsequent challenges with HER2-expressing tumors. Overall, these findings highlight the therapeutic potential of combining T-DXd with macrophage-targeting strategies as a robust approach to improve the efficacy of immunotherapy in HER2-positive cancers, presenting a promising avenue for clinical development.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114378"},"PeriodicalIF":4.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620314","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}
Tian Xie , Yamei Zheng , Lei Zhang, Jie Zhao, Haihong Wu, Yaqing Li
{"title":"PGRN knockdown alleviates pulmonary fibrosis regulating the Akt/GSK3β signaling pathway","authors":"Tian Xie , Yamei Zheng , Lei Zhang, Jie Zhao, Haihong Wu, Yaqing Li","doi":"10.1016/j.intimp.2025.114443","DOIUrl":"10.1016/j.intimp.2025.114443","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary fibrosis (PF) is a serious, chronic, and progressive disease with increased collagen deposition and the collapse of lung structures. Currently, the antifibrotic drugs for PF treatment, nintedanib and pirfenidone, have been proven to reduce the decline of pulmonary function in PF, but both have side effects, and to date, there is no significantly effective treatment to halt the progression of PF. The aim of this study was to investigate the molecular mechanism of pregranuloprotein (PGRN) in pulmonary fibrosis through <em>in vitro</em> and <em>in vivo</em> experiments.</div></div><div><h3>Methods</h3><div>PF models was induced in animals using bleomycin (BLM) and treated MRC-5 cells with TGF-β1. The mRNA expression of PGRN in fasting peripheral blood samples was measured <em>via</em> RT-qPCR and ELSA. PGRN siRNAs were synthesized and transfected into MRC-5 cells. MAZ51, an activator of the Akt/GSK3β pathway, was applied in recovery experiment. The proliferation and apoptosis of MRC-5 cells were determined using the CCK8 kit, MTT kit, and Muse® Cell Analyzer. H&E and Masson staining were applied to evaluate the inflammatory and fibrosis in mouse lung tissue. Levels of PGRN, inflammatory factors (IL-6 and IL-1β), fibrosis markers (α-SMA, COL-I and COL-III), and Akt/GSK3β pathway-related proteins (AKT, GSK-3β and β-catenin) were determined in tissues or cells by ELISA, RT-qPCR, western blot, or Immunofluorescence.</div></div><div><h3>Results</h3><div>PGRN mRNA expression was elevated in the plasma of PF patients. In TGF-β1 induced MRC-5 cells, PGRN knockdown reduced the levels of IL-6, IL-1β, α-SMA, COL-I and COL-III, and suppressed the phosphorylation of AKT and GSK-β. Treatment with MAZ51 partially reversed the effect of PGRN knockdown on TGF-β1-induced PF. Moreover, PGRN knockdown mitigated BLM-induced alveolar destruction and wall thickening, inflammatory cell infiltration, and collagen deposition in mice. It also reduced the expression of α-SMA, TGF-β1, COL-I, COL-III, β-catenin, and the phosphorylation of AKT and GSK-3β in BLM-treated mice.</div></div><div><h3>Conclusions</h3><div>PGRN knockdown alleviates PF <em>in vitro</em> and <em>in vivo</em> by modulating the Akt/GSK3β signaling pathway, proposing that PGRN could serve as a potential therapy or adjuvant therapy for lung fibrosis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114443"},"PeriodicalIF":4.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628030","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}
Duopin Li , Yan Shi , Qi Feng , Fei Tian , Yilin Zhang , Xianpeng Zhang , Chang Liu , Shaokang Pan , Wenjie Sun , Peipei Li , Dongwei Liu , Zhangsuo Liu
{"title":"The PM2.5 component, benzo[b]fluoranthene, may contribute to the pathogenesis of membranous nephropathy by activating phosphoinositide 3-kinase/protein kinase B pathway and causing podocyte pyroptosis","authors":"Duopin Li , Yan Shi , Qi Feng , Fei Tian , Yilin Zhang , Xianpeng Zhang , Chang Liu , Shaokang Pan , Wenjie Sun , Peipei Li , Dongwei Liu , Zhangsuo Liu","doi":"10.1016/j.intimp.2025.114383","DOIUrl":"10.1016/j.intimp.2025.114383","url":null,"abstract":"<div><div>Membranous nephropathy (MN) is the main type of adult nephrotic syndrome, and its prevalence is increasing annually. An increasing number of studies have suggested that the pathogenesis of MN is related to 2.5-μm particulate matter (PM2.5), but the underlying mechanism has not been elucidated fully. Elucidating this mechanism can help prevent and treat MN. The constituents of PM2.5 vary from place to place; hence, the component responsible for PM2.5-related MN is still unclear. This study investigated the effects of benzo[<em>b</em>]fluoranthene (BbF), a PM2.5 component, on pyroptosis and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signalling pathway in Sprague-Dawley rats and mouse podocytes. The organic constituents of BbF in PM2.5 can enter the circulatory system through the lungs and act on the kidneys to cause kidney damage, possibly because BbF activates the PI3K/AKT pathway and causes podocytes to undergo pyroptosis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114383"},"PeriodicalIF":4.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620312","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}
Chunxia Yang , Junzhao Wan , Yan Wang , Ying Yang , Yunsheng Ran , Fenli Zhang , Man Zhou , Ping Liu , Qian Kang , Dan Ma , Xiaoyan Yang
{"title":"UBTF facilitates acute myeloid leukemia development and immune escape via PD-L1 regulation","authors":"Chunxia Yang , Junzhao Wan , Yan Wang , Ying Yang , Yunsheng Ran , Fenli Zhang , Man Zhou , Ping Liu , Qian Kang , Dan Ma , Xiaoyan Yang","doi":"10.1016/j.intimp.2025.114433","DOIUrl":"10.1016/j.intimp.2025.114433","url":null,"abstract":"<div><div>UBTF has been implicated in the development of multiple cancers, yet its specific biological function in acute myeloid leukemia (AML) remains unclear. This study utilized expression profiles and clinical data from The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) databases, with UBTF expression data obtained from the GEPIA database. Analysis via the R software package CIBERSORT explored immune cell infiltration levels under different UBTF expression levels. LASSO Cox analysis with optimized penalty parameters identified genes associated with survival outcomes, leading to the construction of a prognostic risk model using multivariate Cox regression analysis. Prognostic significance was evaluated and validated through Kaplan-Meier survival analysis and receiver operating characteristic curve analysis. Experimental validation using stable AML cell lines with UBTF overexpression or knockdown, transcriptome sequencing, and a CD8<sup>+</sup> T cell killing assay were performed. Ultimately, in vivo experimental validation was conducted. Results revealed that UBTF is overexpressed in AML compared to normal tissues and correlates with poor clinical prognosis. UBTF overexpression is associated with increased expression of PD-L1 (CD274) and immune cell infiltration, suggesting its role in promoting AML progression via PD-L1 (CD274)-mediated immune evasion. These findings highlight UBTF as a potential prognostic biomarker and a novel therapeutic target for tumor immunotherapy in AML.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114433"},"PeriodicalIF":4.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610137","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}
Laiying Liang , Buyun Dang , Xiaomei Ouyang , Xianling Zhao , Yongdong Huang , Ying Lin , Xiaoshen Cheng , Guijing Xie , Junhui Lin , Peng Mi , Zhenyu Ye , Bayasi Guleng , Shih-Chin Cheng
{"title":"Dietary succinate supplementation alleviates DSS-induced colitis via the IL-4Rα/Hif-1α Axis","authors":"Laiying Liang , Buyun Dang , Xiaomei Ouyang , Xianling Zhao , Yongdong Huang , Ying Lin , Xiaoshen Cheng , Guijing Xie , Junhui Lin , Peng Mi , Zhenyu Ye , Bayasi Guleng , Shih-Chin Cheng","doi":"10.1016/j.intimp.2025.114408","DOIUrl":"10.1016/j.intimp.2025.114408","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) remains a pressing global health challenge, necessitating novel therapeutic strategies. Succinate, a metabolite known for its role in type 2 immunity and tuft cell activation in the small intestine, presents its potential in IBD management. However, its impact on colonic inflammation has not been explored. Here, we demonstrate that succinate administration induces a type 2 immune response, significantly alleviating dextran sulfate sodium (DSS)-induced colonic inflammation. Succinate enhances antibacterial capacity, reduces intestinal permeability, and reshapes the colonic cytokine milieu. Mechanistically, succinate promotes myeloid cell expansion in peripheral blood, mesenteric lymph nodes, and the colonic lamina propria. The protective effects of succinate were abolished in <em>Ccr2</em><sup>−/−</sup> mice, confirming the role of monocyte recruitment, but persisted in <em>Rag1</em><sup>−/−</sup> mice, indicating independence from adaptive immunity. Adoptive transfer of monocytes from succinate-treated donors mitigated intestinal inflammation in recipient mice. Transcriptomic analysis revealed heightened expression of <em>Il1b</em> and <em>Il6,</em> and higher lactate production in monocytes upon lipopolysaccharide (LPS) stimulation, highlighting a reprogrammed pro-inflammatory trained immunity phenotype. Finally, we identify the IL-4Rα/Hif-1α axis is critical for succinate-mediated protection. These findings reveal the ability of succinate to reprogram monocytes into protective intestinal macrophages via induction of type 2 response, restoring homeostasis through enhanced barrier function and immune modulation. Our study positions thus uncover succinate as a promising therapeutic candidate for IBD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114408"},"PeriodicalIF":4.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610138","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":"The role of cellular lipid metabolism and lipid-lowering drugs in periodontitis","authors":"Mohammad Kiarashi , Saman Yasamineh","doi":"10.1016/j.intimp.2025.114434","DOIUrl":"10.1016/j.intimp.2025.114434","url":null,"abstract":"<div><div>Initiated by bacteria, periodontitis (PD) is a complex, chronic inflammatory disease of the supporting tissue of the gums and teeth. Also linked to PD include human papillomavirus (HPV), hepatitis B virus (HBV), Epstein–Barr virus (EBV), human cytomegalovirus (CMV), and Herpes Simplex Virus (HSV). PD also raises the risk of cardiovascular disease (CVD) because it triggers inflammatory reactions throughout the body. CVD and chronic PD were linked to significantly elevated levels of C-reactive protein and blood lipids. Furthermore, elevated lipid peroxidation (LPO) levels may influence PD-related inflammation and periodontium degradation. In addition, there was a correlation between a reduction in oxidized low-density lipoprotein (LDL) levels and a reduction in circulating oxidative stress (OS); this was shown to be achieved by improved dental hygiene and non-surgical periodontal treatment. Consequently, this research set out to examine the connections between lipid metabolism and PD, as well as the effects of PD on the efficacy of statins and other medications that decrease cholesterol, as well as inhibitors and other lipid-lowering agents. Additionally, it's worth mentioning that statins and other cholesterol-lowering drugs may affect gum and tooth health. We found that higher blood levels of bad cholesterol exacerbate PD. Furthermore, PD makes CVD worse. The involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in bacterial infections and the development of PD is inversely proportional to the increase in LDL levels. The treatment of this disease could, therefore, benefit greatly by inhibiting this chemical. Medications that lower cholesterol levels may potentially help treat this problem. The possible side effects of this medication on PD patients need more investigation. We have reviewed the literature on PD and its relationship to lipid metabolism, LDL receptors, and lipid rafts. Afterward, we investigated the role of lipid metabolism in the local viral infection that causes PD. Lastly, we examined how statins and other lipid-lowering medications impact PD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114434"},"PeriodicalIF":4.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620461","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}
Jiahong Li , Peicen Zou , Ruiqi Xiao , Yajuan Wang
{"title":"Indole-3-propionic acid alleviates DSS-induced colitis in mice through macrophage glycolipid metabolism","authors":"Jiahong Li , Peicen Zou , Ruiqi Xiao , Yajuan Wang","doi":"10.1016/j.intimp.2025.114388","DOIUrl":"10.1016/j.intimp.2025.114388","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease for which current therapeutic approaches still face many dilemmas, and targeting macrophage polarization and metabolism for the treatment of this disease is a potentially effective strategy. The gut microbial metabolite indole-3-propionic acid (IPA) has favorable anti-inflammatory and antioxidant effects and plays a role in a variety of disease models. IPA is effective in the treatment of UC, but the underlying mechanisms have not been well explored. In the present study, we investigated the mechanisms by which IPA ameliorates colitis in mice from the perspective of macrophage polarization and metabolism. In this study, mice colitis was induced by sodium dextran sulfate and treated with oral IPA. RAW264.7 cells were induced by LPS to polarize into M1 macrophages and treated with IPA. The results showed that IPA could improve colitis by inhibiting M1 polarization of colonic macrophages and promoting M2 polarization. The inhibition of IPA on M1 macrophages was verified in vitro through JNK/MAPK pathway, which inhibited the glycolysis of macrophages. IPA promotes macrophage M2 polarization and enhances fatty acid oxidation through upregulating of CPT1A and ACSL1, which may be related to the activation of PPAR-γ. In summary, IPA can improve colitis by regulating macrophage glucose and lipid metabolism, and targeting intestinal macrophage metabolism may be an effective target for the treatment of UC.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114388"},"PeriodicalIF":4.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620456","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}
Yanlan Wu , Hao Ge , Haoran Zhao , Kaiping Zou , Pei Wang , Yi Wang , Yang Zhang
{"title":"The active ingredient β-sitosterol in the anti-inflammatory agents alleviates perianal inflammation in rats by inhibiting the expression of Srebf2, activating the PPAR signaling pathway, and altering the composition of gut microbiota","authors":"Yanlan Wu , Hao Ge , Haoran Zhao , Kaiping Zou , Pei Wang , Yi Wang , Yang Zhang","doi":"10.1016/j.intimp.2025.114470","DOIUrl":"10.1016/j.intimp.2025.114470","url":null,"abstract":"<div><h3>Background</h3><div>Anti-inflammatory herbal formulations are common in traditional Chinese medicine for clearing heat and detoxifying; however, the specific active components and their mechanisms remain unclear.</div></div><div><h3>Objective</h3><div>This study investigates the role of Sitosterol in alleviating perianal inflammation and its underlying mechanisms.</div></div><div><h3>Methods</h3><div>Sitosterol was identified as a key active ingredient through the TCMSP database. Its structure was analyzed using PubChem, target genes were explored with STITCH, and KEGG pathways related to Srebf2 were revealed by STRING. An animal model of perianal inflammation was induced with 75 % acetic acid and treated with Sitosterol, water, normal saline, or antibiotics. The effects on gut microbiota were assessed using 16S rRNA sequencing, and inflammation was evaluated through HE stains, IHC, and TUNEL assays. In vitro, LPS-treated Caco-2 cells were used to measure proliferation, apoptosis, and cytokine levels, with PPAR pathway involvement examined using GW6471.</div></div><div><h3>Results</h3><div>Sitosterol emerged as the primary active ingredient targeting Srebf2, with KEGG analysis highlighting the PPAR signaling pathway. In rats, Sitosterol reduced weight loss, inflammatory cell infiltration, edema, and vasodilation in perianal tissue. Additionally, it decreased PCNA levels, increased apoptosis, and elevated serum levels of IL-1β, IL-6, and TNF-α, particularly at high doses compared to antibiotics. Sitosterol also restored gut microbiota. Srebf2 knockdown improved tissue conditions and modulated cytokine levels, effects that were countered by GW6471. In LPS-treated Caco-2 cells, Sitosterol reversed reductions in cell viability and proliferation and modulated the expression of proteins and cytokines.</div></div><div><h3>Conclusion</h3><div>Sitosterol restores gut microbiota composition and further alleviates perianal inflammation in rats by inhibiting Srebf2 expression and activating the PPAR signaling pathway.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114470"},"PeriodicalIF":4.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620311","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}
Yun Zhang, Shuhan Shi, Changda Lin, Quanzuan Zeng, Lishuang Che, Yuangen Li, Weiyuan Lin
{"title":"Thiolutin, a novel NLRP3 inflammasome inhibitor, mitigates IgA nephropathy in mice","authors":"Yun Zhang, Shuhan Shi, Changda Lin, Quanzuan Zeng, Lishuang Che, Yuangen Li, Weiyuan Lin","doi":"10.1016/j.intimp.2025.114440","DOIUrl":"10.1016/j.intimp.2025.114440","url":null,"abstract":"<div><div>NLRP3 inflammasome plays a key role in IgA Nephropathy (IgAN) pathogenesis. Thiolutin (THL) is an NLRP3 inflammasome inhibitor with anti-inflammatory effects, but its role in IgAN is unclear. This study aimed to evaluate the protective efficacy of THL in IgAN mice, alongside assessing its inhibitory mechanisms. IgAN was induced by administration of bovine serum albumin combined with Staphylococcal Enterotoxin B in mice, followed by THL treatment. Kidney injury biomarkers, inflammatory cytokines, histological changes and the NLRP3 inflammasome pathway were assessed. The effect of THL on pyroptosis and action site on inflammasome was examined in J774A.1 cells, and co-immunoprecipitation was used to study specific protein interactions. In IgAN mice, THL treatment significantly reduced renal dysfunctional markers and histological injury without affecting hepatic function, accompanied by decreased serum IgA levels, renal IgA deposition and pro-inflammatory cytokine accumulation via regulating the mRNA and protein expression of key inflammasome components. It also attenuated pyroptosis and NLRP3 inflammasome activation instead of priming in macrophages, via disturbing the combination of NLRP3 with apoptosis-associated speck-like protein and NIMA-Related Kinase 7. THL has significant anti-inflammatory and renal protective effects in IgAN via inhibiting the NLRP3 inflammasome pathway. Its selective impact on the activation and assembly of the inflammasome, without affecting priming, highlights its potential as a targeted therapeutic agent in IgAN management.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"152 ","pages":"Article 114440"},"PeriodicalIF":4.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610140","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}