International immunopharmacology最新文献

{"title":"Hydroxysafflor yellow A attenuates the inflammatory response in cerebral ischemia-reperfusion injured mice by regulating microglia polarization per SIRT1-mediated HMGB1/NF-κB signaling pathway.","authors":"Min Yao, Yuting Liu, Dongdong Meng, Xian Zhou, Dennis Chang, Lili Li, Ning Wang, Qi Huang","doi":"10.1016/j.intimp.2025.114040","DOIUrl":"10.1016/j.intimp.2025.114040","url":null,"abstract":"<p><strong>Background: </strong>Hydroxysafflor yellow A (HSYA), an active component isolated from Carthamus tinctorius L., has demonstrated potent protective effects against cerebral ischaemia/reperfusion (I/R) injury. Microglial polarisation plays a crucial role in I/R. However, the mechanism by which HSYA regulates microglial polarisation remains unclear.</p><p><strong>Objective: </strong>To explore the mechanism of action of HSYA on the phenotypic polarisation of microglia stimulated by lipopolysaccharide (LPS) in a mouse model of I/R injury.</p><p><strong>Methods: </strong>BV2 cells injured by LPS and a modified middle cerebral artery occlusion/reperfusion (MCAO/R) model were used to mimic I/R in vitro and in vivo, respectively. BV2 cell morphology was assessed by optical microscopy, and cell viability was evaluated using the CCK-8 assay. The effect of HSYA on MCAO/R mice was assessed using the Longa assay, brain index, triphenyl tetrazolium chloride, and haematoxylin and eosin staining. LDH, NO, IL-6, TNF-α, and IL-10 levels were measured using corresponding ELISA kits following the manufacturers' protocols. M1 and M2 type microglia markers, including CD86, CD16/32, iNOS, YM1/2, TGF-β, and Arg, were detected by western blotting. M1 and M2 cell surface markers (CD86 and CD206) were detected using immunofluorescence. Molecular docking, DARTS, and CETSA were applied to investigate the interactions between HSYA and SIRT1. The role of HSYA in regulating the binding of HMGB1 to SIRT1 was tested using co-immunoprecipitation. Proteins related to the HMGB1/NF-κB pathway were also analysed by western blotting.</p><p><strong>Results: </strong>HSYA promoted microglial polarisation from M1 to M2 type in LPS-induced BV2 cells and MCAO/R mice. HSYA significantly reduced M1 polarisation markers, including IL-6, TNF-α, CD86, CD16/32, while increasing the expression of IL-10, Arg, YM1/2, TGF-β. Furthermore, compared to the MCAO/R group, HSYA significantly improved neurological scores, brain index, and infarct volume and normalised nucleolar arrangement. Molecular docking assessment showed that HSYA exhibited strong binding SIRT1 and significantly improved the interactions between SIRT1 and HMGB1. HSYA also decreased the expression of cytoplasm-HMGB1 and reduced the P-P65/P65 ratio.</p><p><strong>Conclusions: </strong>HSYA attenuates LPS-induced and MCAO/R-induced inflammatory responses by modulating microglia polarisation. This effect is associated with the SIRT1-mediated HMGB1/NF-κB signalling pathway.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"114040"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970789","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":"Deletion of BMP4 impairs trophoblast function and decidual macrophage polarization via autophagy leading to recurrent spontaneous abortion.","authors":"Lujia Tang, Fangfang Dai, Yuwei Zhang, Ruiqi Wang, Wei Tan, Ran Gu, Liping Chen, Linlin Wang, Hua Liu, Yanxiang Cheng, Liangbin Xia","doi":"10.1016/j.intimp.2025.114015","DOIUrl":"10.1016/j.intimp.2025.114015","url":null,"abstract":"<p><p>Bone morphogenetic protein 4 (BMP4) is widely involved in the regulation of cell proliferation and differentiation, but its role in Recurrent Spontaneous Abortion (RSA) remains unclear. RSA is a disease that affects roughly 1-2% of partner pairs, but its pathogenesis is still unclear. In recent years, many studies have focused on the role of decidual macrophages in RSA. In this study, we found decreased expression levels of BMP4 in villous tissues of RSA patients and found that low expression of RUNX2 leads to down-regulation of BMP4, which impairs trophoblast function. More importantly, we found in both co-culture system and human recombinant BMP4 protein models that BMP4 overexpression polarizes THP-1-derived macrophages toward M2, and down-regulation of BMP4 leads to macrophage polarization toward M1. Mechanically, we found that BMP4 promotes macrophage polarization via regulating autophagy level. The recovery experiment was further confirmed that 3-MA (autophagy inhibitor) inhibit THP-1-derived macrophage polarization toward M2 induced by BMP4 overexpression and exogenous addition of rBMP4, and rapamycin (autophagy agonists) inhibit macrophages polarization toward M1 from down-regulation of BMP4. Our study further reveals the mechanism of maternal-fetal interface cell interactions in RSA, which can help in the diagnosis and treatment of RSA.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"114015"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978333","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":"Understanding the relationship between silicone implants, tumor antigens, and breast cancer risk: An immunological study in rats.","authors":"Yu Zhou, Zihao Li, Gaoyi Wang, Hua Yu, Yaqin Zhou, Yijun Li, Wanying Chen, Hao Dai, Yucang He, Liqun Li","doi":"10.1016/j.intimp.2024.113991","DOIUrl":"10.1016/j.intimp.2024.113991","url":null,"abstract":"<p><p>This study aimed to investigate the effects of silicone implants on the incidence of breast cancer in rats, as well as their impact on immune surveillance mechanisms. Female SD rats were divided into three groups: a Placebo Surgery Group (PSG), a Thoracic Implant Group (TIG), and a Back Implant Group (BIG). Following the corresponding surgical procedures, we measured Secretoglobin Family 2A, Member 2(SCGB2A2) and Mucin-1 (MUC1) antigen levels using ELISA, and statistical analyses were conducted to evaluate immune responses. The N-Methyl-N-Nitrosourea(MNU)-induced breast cancer model and pathological analyses indicated that the incidence of breast cancer in the thoracic implant group was lower, suggesting that silicone implants may reduce the risk of breast cancer. Additionally, laser speckle blood flow imaging and immunohistochemical analysis revealed blood perfusion in the implant capsule area and an active response of immune cells, indicating that immune surveillance may exert local effects. These findings provide the first evidence of a relationship between tumor antigens, silicone implants, and breast cancer incidence, offering a new immunological perspective on the safety of silicone implants.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"113991"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978337","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":"GDF11 improves cardiac repair after myocardial infarction by reducing Macrophage infiltration and attenuating their inflammatory Properties","authors":"Shushi Huang ,&nbsp;Yuling Wu ,&nbsp;Mingyao Chen ,&nbsp;Jiahua Shen ,&nbsp;Jinyun Zhu ,&nbsp;Hong Yu","doi":"10.1016/j.intimp.2024.113994","DOIUrl":"10.1016/j.intimp.2024.113994","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113994"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051856","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":"Inhibition of SIRT4 promotes bladder cancer progression and immune escape via attenuating CD8+ T cells function","authors":"Jiancheng Lv ,&nbsp;Yu Zhang ,&nbsp;Qikai Wu ,&nbsp;Peng Jiang ,&nbsp;Yiwei Lin","doi":"10.1016/j.intimp.2024.113906","DOIUrl":"10.1016/j.intimp.2024.113906","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Bladder cancer (BCa) is one of the most common malignancies of the urinary system and is characterized by a high recurrence rate and significant mortality. Sirtuin 4 (SIRT4), a member of the NAD&lt;sup&gt;+&lt;/sup&gt;-dependent deacetylase and ADP-ribosyltransferase family, is involved in regulating cellular metabolism, DNA repair, and longevity, potentially influencing tumor progression and immune escape. This study aimed to elucidate the role of SIRT4 in BCa.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The correlation between the sirtuin family and immunotherapy sensitivity in BCa patients was analyzed via IMvigor210 data. The clinical significance and immunological role of SIRT4 across multiple cancer types were assessed by evaluating its associations with clinicopathologic features, prognosis, tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration, and immune response genes across 33 datasets from The Cancer Genome Atlas (TCGA). SIRT4 expression was confirmed in BCa tissues, and its functions were examined via proliferation and migration assays. CD8&lt;sup&gt;+&lt;/sup&gt; T cells were isolated from the peripheral blood of healthy individuals and activated with CD3 and CD28 antibodies and recombinant IL2. Coculture assays involving BCa cells and activated CD8&lt;sup&gt;+&lt;/sup&gt; T cells, alongside ELISA, were conducted to evaluate the immunological function of SIRT4.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;SIRT4 was positively associated with the immunotherapy response of BCa patients on the basis of IMvigor210 data. Its expression was downregulated in 11 tumor types but upregulated in 3. SIRT4 was significantly correlated with tumor stage in 2 tumor types and showed varying associations with overall survival, progression-free survival, and disease-specific survival. Additionally, SIRT4 was correlated with TMB in 10 tumor types and with MSI in 8. GSEA indicated that SIRT4 was negatively associated with the immune response in 9 tumor types, excluding BCa. It was positively correlated with immune cell infiltration in 2 tumor types and negatively correlated in 6. The TCGA data revealed that SIRT4 was positively associated with activated NK cell infiltration but negatively associated with M1 macrophages, neutrophils, resting NK cells, and activated memory CD4 T cells. Enrichment analyses revealed positive correlations with various chemokines, immunoinhibitors, immunostimulators, lymphocytes, MHC molecules, and MHC receptors, suggesting that SIRT4 may enhance the immune response in BCa. Further experiments confirmed that SIRT4 was downregulated in BCa tissues compared with adjacent normal tissues. Inhibition of SIRT4 promoted BCa cell proliferation and migration, whereas knockdown of SIRT4 impaired the chemotaxis and tumor-killing ability of CD8&lt;sup&gt;+&lt;/sup&gt; T cells in the BCa tumor microenvironment.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;In summary, SIRT4 inhibits the progression and immune escape of BCa, indicating its pote","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113906"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931610","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":"Maackiain induces apoptosis and autophagy via ROS-mediated endoplasmic reticulum stress in endometrial cancer","authors":"Yijuan Xing ,&nbsp;Xiao Lv ,&nbsp;Xi Chen ,&nbsp;Junhong Du ,&nbsp;Dan Hu ,&nbsp;Ruifen He ,&nbsp;Xiaolei Liang ,&nbsp;Yongxiu Yang","doi":"10.1016/j.intimp.2024.113935","DOIUrl":"10.1016/j.intimp.2024.113935","url":null,"abstract":"<div><div>Endometrial cancer (EC) is a common gynecological cancer, characterized by increasing incidence and mortality rates. Maackiain (MA), a natural flavonoid compound, has multiple biological activities, but little is known about how it affects EC cells. In the present study, CCK-8, EdU, colony formation, and flow cytometry assays were used to evaluate the effects of MA on EC cell proliferation, apoptosis, and reactive oxygen species (ROS) levels. The effect of MA on autophagy in EC cells were examined through the observation of cell morphology and ultrastructure, and cells were transfected with AdPlus-mCherry-GFP-LC3B for further analysis. Transcriptomic and western blot analyses revealed the underlying mechanism. To evaluate the anti-EC effect of MA in vivo, a xenograft model was established. The results demonstrated that MA inhibited KLE and Ishikawa cell growth in a dose-dependent manner. Furthermore, MA significantly suppressed EC xenograft tumor growth in vivo while exhibiting low toxicity. In addition, EC cells treated with MA exhibited pro-apoptotic and pro-autophagic responses, with the latter exhibiting cytoprotective properties. MA also induced the accumulation of ROS, which promoted endoplasmic reticulum (ER) stress. Notably, the use of the N-acetyl-L-cysteine (NAC) ROS scavenger and the 4-phenylbutyric acid (4-PBA) ER stress inhibitor effectively mitigated the autophagy and apoptosis induced by MA. These results collectively implied that MA triggers autophagy and apoptosis in EC cells through ROS-mediated ER stress, highlighting its potential as a therapeutic agent against EC.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113935"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931612","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":"Bergenin inhibits ferritinophagy and ferroptosis in cisplatin-induced acute kidney injury by activating the p-GSK3β/Nrf2/PPARγ pathway","authors":"Jianqiang Hu ,&nbsp;Yan Zhang ,&nbsp;Yanmin Zhang,&nbsp;Ningmohan Shi,&nbsp;Yufan Miu,&nbsp;Jing Huang,&nbsp;Mochi Miao,&nbsp;Xinxin Ci","doi":"10.1016/j.intimp.2024.114004","DOIUrl":"10.1016/j.intimp.2024.114004","url":null,"abstract":"<div><div>Ferroptosis plays a key role in cisplatin-induced acute kidney injury (AKI). Bergenin, which is extracted from Ardisiae Japonicae Herba and has long been used in folk tea and herbal tea drinks, is known to activate Nrf2 and has anti-inflammatory and antioxidant properties, however, its protective influence on CI-AKI has not been elucidated. We used models of cisplatin-induced nephrotoxicity in vitro and CI-AKI models in vivo. In vitro, we found that ferroptosis and ferritinophagy biomarkers were strongly regulated by bergenin treatment. Mechanistic experiments demonstrated that bergenin bound to and phosphorylated GSK3β, which inhibited its activity, to promote the nuclear translocation of Nrf2 and its subsequent binding to the PPARγ promoter sequence to activate PPARγ. However, the protective effects of bergenin on ferroptosis and ferritinophagy in cisplatin-exposed HK-2 cells were diminished when Nrf2 or PPARγ was inhibited. In vivo, bergenin effectively inhibited renal damage induced by cisplatin. Furthermore, bergenin attenuated ferritinophagy-mediated ferroptosis caused by cisplatin; these effects were abolished in Nrf2 knockout mice. Our findings revealed that bergenin effectively protected against ferritinophagy and ferroptosis in CI-AKI, which was largely dependent on the activation of the p-GSK3β/Nrf2/PPARγ pathway.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114004"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964530","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":"Regulation of 5-fluorouracil-induced intestinal damage by the interleukin-23/interleukin-22 axis in chemotherapy","authors":"Yongquan Han ,&nbsp;Jingping Xu ,&nbsp;Yuxuan Zhang ,&nbsp;Junqi Sun ,&nbsp;Yan Huang ,&nbsp;Fang Cai ,&nbsp;Yunxiang Ji ,&nbsp;Long Zhang ,&nbsp;Yezhong Wang","doi":"10.1016/j.intimp.2025.114044","DOIUrl":"10.1016/j.intimp.2025.114044","url":null,"abstract":"<div><div>5-Fluorouracil (5-FU) is a primary chemotherapeutic agent for gastrointestinal cancers, known to improve survival but also cause significant intestinal damage, affecting patient quality of life. This study investigated the IL-23-IL-22 axis’s role in moderating 5-FU-induced intestinal damage. We analyzed paracancerous tissue damage in colon cancer patients with different Tumor Regression Grade (TRG) and found a direct correlation between TRG and tissue damage severity, indicating that higher chemotherapy effectiveness is linked to increased tissue damage. In a 5-FU-treated mouse model, we observed severe intestinal damage and a reduction in proliferative cells. Transcriptome sequencing and immunofluorescence revealed that myeloid cells in damaged tissues produced IL-23, which activated ILC3s to secrete IL-22, promoting tissue repair and homeostasis. IL-22 supplementation in deficient mice significantly mitigated damage, underscoring the IL-22/IL-23 axis’s potential as a therapeutic target to reduce chemotherapy-induced damage and enhance recovery. This research advances understanding of the biochemical responses to chemotherapy and suggests new avenues for developing therapies to maintain intestinal integrity during cancer treatment.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114044"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964551","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":"Comprehensive characteristics of pulmonary antineutrophil cytoplasmic antibody-associated vasculitis and the development of a predictive nomogram for mortality","authors":"Min Qi ,&nbsp;Yongjiang Tang ,&nbsp;Haixia Zhou ,&nbsp;Maoyun Wang ,&nbsp;Qun Yi ,&nbsp;Zongan Liang ,&nbsp;Jian-Qing He","doi":"10.1016/j.intimp.2024.113986","DOIUrl":"10.1016/j.intimp.2024.113986","url":null,"abstract":"<div><h3>Objectives</h3><div>Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a rare and potential devastating disease with high mortality, frequently with pulmonary involvement. Our study aimed to explore the pulmonary features of AAV and identify predictors of long-term survival.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed 538 AAV patients diagnosed between January 2013 and July 2019, with follow-up data extending to August 2020. The Least absolute shrinkage and selection operator (LASSO) regression analysis was employed to identify variables predictive of mortality. Subsequently, a nomogram was developed, with its predictive accuracy and discrimination assessed by the concordance index and calibration curves, respectively.</div></div><div><h3>Results</h3><div>A total of 460 (85.5 %) AAV patients presented with pulmonary involvement. The mortality was 36.8 %. Patients with pulmonary involvement more frequently exhibited respiratory symptoms, predominantly interstitial lung disease on radiographs, and were at higher risk for respiratory failure, diffuse alveolar hemorrhage, mechanic ventilation and death (All <em>P</em> &lt; 0.05). The LASSO regression pinpointed 16 predictors of mortality, and the predictive model demonstrated an area under the curve of 0.810. The nomogram, based on these variables, achieved a concordance index of 0.825, with calibration curve indicating excellent predictive agreement.</div></div><div><h3>Conclusion</h3><div>The study establishes a predictive model for AAV mortality with high accuracy, offering insights crucial for patient care. Pulmonary involvement, prevalent and linked to higher mortality, underscores the need for precise predictive tools in AAV management.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113986"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927168","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":"Effects of dioscin from Dioscorea nipponica on TL1A/DR3 and Th9 cells in a collagen-induced arthritis mouse model","authors":"Yaxian Gao ,&nbsp;Dongshuai Xia ,&nbsp;Yong You ,&nbsp;Yu Cheng ,&nbsp;Bing Bai ,&nbsp;Guiying Feng ,&nbsp;Xiujun Liang ,&nbsp;Luyang Cheng ,&nbsp;Hongru Song ,&nbsp;Yongwei Wang","doi":"10.1016/j.intimp.2025.114028","DOIUrl":"10.1016/j.intimp.2025.114028","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a systemic autoimmune disease, and TL1A and its receptor DR3 play important roles in its pathogenesis. Th9 cells are involved in RA development. Dioscin from Dioscorea nipponica (DDN) has a therapeutic effect on RA, but its effect on TL1A/DR3 and Th9 cells remains unclear. A collagen-induced arthritis (CIA) model was established in DBA/1 mice, and the therapeutic effects of DDN were determined using pathological sections and arthritis index scores. Western blotting and PCR were used to detect TL1A, DR3, PU.1, TGF-β and IRF-4. Enzyme-linked immunosorbent assay was used to detect the expression of TL1A and IL-9 in the serum. Immunofluorescence was used to detect the localization and expression of TL1A, DR3, and PU.1 in synovial tissue. Flow cytometry was used to detect TL1A and DR3 expression in different immune cells and Th9 cells. DDN ameliorated bone destruction, inflammatory cell infiltration, synovial inflammation, cartilage tissue destruction, and proteoglycan loss. DDN downregulated TL1A, DR3, and PU.1 in the synovium of the lymph nodes and spleen and TL1A and IL-9 in the serum. DDN decreased the number of TL1A-expressing APCs and macrophages, DR3-expressing CD4 + T cells, and Th9 cells. Th9 cell differentiation-related factors TGF-β and IRF-4 were also inhibited by DDN. We conclude that DNN inhibited the expression of TL1A/DR3 in CIA mice and suppressed the expression of the Th9 cell-specific transcription factor PU.1, Th9 cell number, and IL-9 secretion. DDN inhibited the function of Th9 cells by targeting TGF-β and IRF-4 in the TL1A/DR3 pathway, thereby reducing inflammation.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114028"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970785","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}