Inflammation最新文献_第3页

PARP1 Exacerbates Prostatitis by Promoting M1 Macrophages Polarization through NF-κB Pathway.

IF 4.5 2区医学

Inflammation Pub Date : 2025-03-04 DOI: 10.1007/s10753-025-02247-y

Lu Jin, Jiaxing Chen, Jianhui Fu, Jingyi Lou, Yingxue Guo, Xia Liu, Xiaojuan Xu, Huiying Fu, Qiyang Shou

{"title":"PARP1 Exacerbates Prostatitis by Promoting M1 Macrophages Polarization through NF-κB Pathway.","authors":"Lu Jin, Jiaxing Chen, Jianhui Fu, Jingyi Lou, Yingxue Guo, Xia Liu, Xiaojuan Xu, Huiying Fu, Qiyang Shou","doi":"10.1007/s10753-025-02247-y","DOIUrl":"https://doi.org/10.1007/s10753-025-02247-y","url":null,"abstract":"PARP1 is recognized for its role as a DNA damage sensor and its involvement in inflammatory diseases, but its impact on prostatitis remains unclear. We aimed to elucidate how PARP1 affects prostatitis progression. Our results showed that in 1% carrageenan-induced prostatitis mouse model, Parp1-/- prostatitic mice showed less pathological damage, decreased prostate weight, and lower inflammatory indices, decreased macrophage and neutrophil infiltration, down-regulated the expression of pro-inflammatory cytokines (IL-6, IL-12p70, CCL2, TNF) and up-regulated anti-inflammatory cytokine IL-10 in prostate tissue. The expression of NF-κB, TNF, and IL-6 mRNA in the prostate tissue of Parp1-/- prostatitic mice decreased. In vitro experiments revealed that M1(CD206-CD86+) macrophage in LPS-induced macrophage of Parp1-/- mice decreased, as did iNOS, TNF, IL-6 and NF-κB mRNA expression. Mechanically, treatment with the PARP1 inhibitor (AG14361) led to a significant reduction in NF-κB mRNA and Phospho-NF-κB P65 protein expression in macrophages. Following intervention with NF-κB inhibitors (Bay 11-7082), both IL-6 protein and mRNA levels were markedly diminished, meanwhile the secretion of IL-6, IL-10, IL-12p70, CCL2, IFN-γ, and TNF exhibited a pronounced dose-dependent decrease. Collectively, these findings indicated that PARP1 exacerbates carrageenan-induced prostatitis by promoting M1 macrophages polarization via the NF-κB pathway, suggesting PARP1 could be a potential therapeutic target for macrophage-based treatments in prostatitis.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541664","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}

引用次数: 0

DNAJB2 Attenuates Rosacea Skin Inflammation and Angiogenesis by Inhibiting the Endoplasmic Reticulum Stress-mediated TLR2/Myd88/NF-κB pathway.

IF 4.5 2区医学

Inflammation Pub Date : 2025-03-04 DOI: 10.1007/s10753-025-02278-5

Yuxin Qing, Jiawen Wu, Bingyang Xu, Zining Xu, Shuhong Ye, Yuanqin Wang, Bin Zhao, Hong Sun, Na Wu

{"title":"DNAJB2 Attenuates Rosacea Skin Inflammation and Angiogenesis by Inhibiting the Endoplasmic Reticulum Stress-mediated TLR2/Myd88/NF-κB pathway.","authors":"Yuxin Qing, Jiawen Wu, Bingyang Xu, Zining Xu, Shuhong Ye, Yuanqin Wang, Bin Zhao, Hong Sun, Na Wu","doi":"10.1007/s10753-025-02278-5","DOIUrl":"https://doi.org/10.1007/s10753-025-02278-5","url":null,"abstract":"Endoplasmic reticulum stress (ERS) has recently been proposed as a core factor in the pathogenesis and aggravation of rosacea. The roles of ERS-related genes in rosacea are largely unknown and were investigated in this study. Rosacea microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed ERS-related genes in rosacea patients vs. controls were screened using the Limma package, and LASSO regression was used to screen for characteristic genes. The infiltrating fraction was evaluated using ssGSEA. Clinical rosacea samples, age-matched healthy volunteers, and LL37-induced mice models were used to investigate the expression of DNAJB2 and its function. In the GSE65914 dataset, 17 differentially expressed ERS-related genes were screened. Of these, 13 were identified as characteristic genes predicting rosacea risk. The adaptive immune response, TLR signaling pathway, and chemokine signaling pathway were activated with a high risk of rosacea. After expression validation using the GSE155141 dataset, DNAJB2 was identified as a key gene. DNAJB2 expression was significantly decreased in both datasets, clinical samples, and the LL37-induced mice model. DNAJB2 overexpression could alleviate rosacea skin injury and inhibit expression of inflammatory cytokines and chemokines as well as angiogenesis. The infiltration levels of the majority of immune cell types were elevated in rosacea samples, and DNAJB2 overexpression inhibited CD4 + T cell infiltration, as well as Th1 and Th17 polarizing genes. Moreover, DNAJB2 could inhibit ERS marker proteins and the activated TLR2/Myd88/NF-κB pathway. DNAJB2 may be a novel target for rosacea treatment.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541355","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}

引用次数: 0

Plasma Exosomes Derived from Patients with Primary Immune Thrombocytopenia Attenuate TBX21⁺ Regulatory T Cell-Mediated Immune Suppression via MiR-363-3p.

IF 4.5 2区医学

Inflammation Pub Date : 2025-03-04 DOI: 10.1007/s10753-025-02275-8

Yuanlan Huang, Peng Liu, Ying Xu, Cheng Qian, Tianqin Wu, Tengda Li

{"title":"Plasma Exosomes Derived from Patients with Primary Immune Thrombocytopenia Attenuate TBX21+ Regulatory T Cell-Mediated Immune Suppression via MiR-363-3p.","authors":"Yuanlan Huang, Peng Liu, Ying Xu, Cheng Qian, Tianqin Wu, Tengda Li","doi":"10.1007/s10753-025-02275-8","DOIUrl":"https://doi.org/10.1007/s10753-025-02275-8","url":null,"abstract":"Primary Immune Thrombocytopenia (ITP) is characterized by reduced immunosuppressive function of regulatory T cells (Tregs), contributing to immune imbalance and decreased platelet counts. However, the mechanisms behind this reduced efficacy of Tregs remain unclear. Our study used a variety of methods, including Treg function assays, cytokine analysis, and single-cell sequencing, to explore these mechanisms. We found that exosomes from ITP patients inhibited TBX21 expression in Tregs, and impaired their ability to suppress Th1 cells. At the single-cell level, Tregs with high TBX21 expression were identified, and the activity of the TBX21 regulon was found to be enhanced in early-stage Treg subpopulations. We also discovered that ARID3A interacted with SPI1 and TBX21 gene regions, indicating a regulatory relationship between ARID3A, SPI1, and TBX21. Additionally, exosomes in ITP patients' plasma contained elevated levels of miR-363-3p, which negatively correlated with platelet count. These exosomes transferred miR-363-3p to Tregs, downregulating ARID3A, SPI1, and TBX21 expression, thereby weakening Tregs' ability to suppress conventional CD4 + T cells. In conclusion, exosomes from ITP patients reduced Treg function through the ARID3A/SPI1/TBX21 axis by miR-363-3p, diminishing their ability to regulate Th1 cells and contributing to the immune dysfunction observed in ITP.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541672","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}

引用次数: 0

NLRP3-inflammasome Related Genes as Emerging Biomarkers and Therapeutic Targets in Psoriasis.

IF 4.5 2区医学

Inflammation Pub Date : 2025-03-03 DOI: 10.1007/s10753-025-02271-y

Ao Shi, Yuan Shu, Kaibo Hu, Shivon Sudesh, Ying Tu

{"title":"NLRP3-inflammasome Related Genes as Emerging Biomarkers and Therapeutic Targets in Psoriasis.","authors":"Ao Shi, Yuan Shu, Kaibo Hu, Shivon Sudesh, Ying Tu","doi":"10.1007/s10753-025-02271-y","DOIUrl":"https://doi.org/10.1007/s10753-025-02271-y","url":null,"abstract":"The NLRP3 inflammasome is closely associated with inflammatory diseases, including psoriasis. Objective diagnostic biomarkers and alternative therapies for psoriasis remain limited. We aimed to identify reliable biomarkers for the diagnosis of psoriasis and investigate potential therapy strategies. Machine learning methods were performed in over 1000 skin samples from public transcriptome database to identify NLRP3 inflammasome-related biomarkers. Multivariate Cox regression analysis was used to establish the biomarker-based diagnostic model. TNF-induced HaCaT cell model was used to evaluate biomarker-related inflammatory changes. Biomarker-targeting drugs was predicted with NetworkAnalyst database and validated in imiquimod (IMQ)-induced mouse model. Elevated level of four NLRP3 inflammasome-related biomarkers, including NLRP3, ASC, TXNIP and CASP-1, were identified from the public psoriasis transcriptome samples and validated in our local psoriasis skin biopsies. The biomarker-based diagnostic model was developed from training dataset and validation dataset, which both showed significant diagnostic value for psoriasis. Knocking down one of these genes in vitro showed reduced inflammatory factors, reduced cell apoptosis and improved cell viability. Furthermore, Predictive biomarker-targeting therapeutics, including resveratrol and JQ-1, demonstrated effective alleviation of psoriasis severity and reduced inflammation in IMQ-induced psoriasis mice. Combinational evaluation of NLRP3, ASC, TXNIP and CASP-1 may constitute a novel diagnostic approach for psoriasis. Targeting these proteins provide more options for psoriasis therapy.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541459","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}

引用次数: 0

Inhibition of Cullin3 Neddylation Alleviates Diabetic Retinopathy by Activating Nrf2 Signaling to Combat ROS-Induced Oxidative Stress and Inflammation.

IF 4.5 2区医学

Inflammation Pub Date : 2025-03-01 DOI: 10.1007/s10753-025-02259-8

Yueqin Chen, Cong Liu, Jun Tong, Chang He, Xinru Ling, Jinjin Xiang, Chunyan Xue, Genhong Yao, Lingyun Sun, Zhenggao Xie

{"title":"Inhibition of Cullin3 Neddylation Alleviates Diabetic Retinopathy by Activating Nrf2 Signaling to Combat ROS-Induced Oxidative Stress and Inflammation.","authors":"Yueqin Chen, Cong Liu, Jun Tong, Chang He, Xinru Ling, Jinjin Xiang, Chunyan Xue, Genhong Yao, Lingyun Sun, Zhenggao Xie","doi":"10.1007/s10753-025-02259-8","DOIUrl":"https://doi.org/10.1007/s10753-025-02259-8","url":null,"abstract":"Oxidative stress and inflammation induced by reactive oxygen species (ROS) play important roles in the development of diabetic retinopathy (DR). Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which is negatively controlled by Cullin3-RING E3 ligase (CRL3) and controls ROS levels, is compromised in DR. CRL3 activity is regulated by Cullin3 neddylation. Nonetheless, the relationship between Cullin3 neddylation and DR remains uncertain. The goal of this study was to evaluate the effect of Cullin3 neddylation on DR and its underlying mechanisms by utilizing MLN4924, a neddylation inhibitor. Cullin3 neddylation was elevated in diabetic rats' retinas as well as in advanced glycation end products (AGEs)-induced endothelial cells. Inhibiting neddylation of Cullin3 with MLN4924 downregulated Nrf2 ubiquitination, promoted Nrf2 accumulation, suppressed ROS-induced oxidative stress and inflammation, and attenuated blood-retinal barrier (BRB) breakdown in both diabetic vivo and vitro models. However, the beneficial impact of MLN4924 was compromised when Nrf2 was suppressed with siRNA in vitro. This study showed that inhibition of Cullin3 neddylation with MLN4924 exerted protective effect on DR by activating Nrf2 signaling to inhibit ROS-induced retinal injury, which indicated that targeting Cullin3 neddylation could be a promising treatment option for DR.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531448","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}

引用次数: 0

Clonorchis sinensis Infection prevents DSS-induced Colitis Via Lithocholic Acid in a Gut Microbiota-Dependent Manner.

IF 4.5 2区医学

Inflammation Pub Date : 2025-02-27 DOI: 10.1007/s10753-025-02241-4

Beibei Zhang, Na Xu, Zheng-Rui Bian, Chen Zhang, Xing Li, Xin-Xin Ren, Zhihua Jiang, Zhongdao Wu, Qian Yu, Kui-Yang Zheng, Mu-Xin Chen, Chao Yan

{"title":"Clonorchis sinensis Infection prevents DSS-induced Colitis Via Lithocholic Acid in a Gut Microbiota-Dependent Manner.","authors":"Beibei Zhang, Na Xu, Zheng-Rui Bian, Chen Zhang, Xing Li, Xin-Xin Ren, Zhihua Jiang, Zhongdao Wu, Qian Yu, Kui-Yang Zheng, Mu-Xin Chen, Chao Yan","doi":"10.1007/s10753-025-02241-4","DOIUrl":"https://doi.org/10.1007/s10753-025-02241-4","url":null,"abstract":"Increasing evidence demonstrates that helminth and its components can ameliorate ulcerative colitis. Clonorchis sinensis (C. sinensis) is a kind of helminth that dwells in the bile ducts for many years, but the roles and underlying mechanisms of C. sinensis-induced protection from colitis are not elucidated. In the present study, the mice were infected with 50 C. sinensis metacercariae and further administrated with 4% Dextran Sodium Sulfate (DSS) in drinking water for 7 days on days 49 post-infection. The disease severity and the integrity of gut barriers were evaluated. Gut microbiota was measured using 16sRNA sequencing, and bile acids in the colon were detected by Liquid Chromatography Mass Spectrometry (LC/MS). The Co-housing approach or microbiota deletion with additional supplies of secondary bile acids (SBAs) was employed to investigate the roles of gut microbiota in the protection from colitis. C. sinensis infection moderated the dysbiosis of the intestinal microbiota and increased the levels of SBAs and bile acid receptor Takeda G protein-coupled receptor 5 (TGR5), which finally benefited anti-inflammation and ameliorated the severity of DSS-induced colitis. Co-housing with C. sinensis-infected mice, and non-infected mice with colitis also showed an increase of TGR5, decreased pro-inflammatory cytokines, and a reduction in the severity of colitis, compared to those mice suffering from colitis without co-housing. Furthermore, C. sinensis-induced protective effects on colitis were attenuated by microbiota deletion, while SBAs (lithocholic acid, LCA) supplementation reversed the colitis. The present study demonstrates that C. sinensis infection ameliorates DSS-induced ulcerative colitis in mice, which is dependent on gut microbiota-associated SBAs.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515491","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}

引用次数: 0

Microbiological and Metabolomic Analysis of Biomarkers for Grades A and B in Stage II Periodontitis.

IF 4.5 2区医学

Inflammation Pub Date : 2025-02-27 DOI: 10.1007/s10753-025-02260-1

Wenjie Dai, Yuhan Ye, Bingyong Mao, Xin Tang, Shumao Cui, Jianxin Zhao, Chenchen Feng, Qiuxiang Zhang

{"title":"Microbiological and Metabolomic Analysis of Biomarkers for Grades A and B in Stage II Periodontitis.","authors":"Wenjie Dai, Yuhan Ye, Bingyong Mao, Xin Tang, Shumao Cui, Jianxin Zhao, Chenchen Feng, Qiuxiang Zhang","doi":"10.1007/s10753-025-02260-1","DOIUrl":"https://doi.org/10.1007/s10753-025-02260-1","url":null,"abstract":"Periodontitis is a chronic inflammatory disease characterized by inflammation of the periodontal soft tissues and loss of alveolar bone. In the oral environment, subgingival microorganisms and salivary metabolites reflect the host's health status. This study aimed to understand periodontitis severity and progression rate by analyzing subgingival microflora and salivary metabolites to identify potential biomarkers. Fifty-three volunteers with stage II periodontitis were graded using the bone loss (%)/age index into two grades: 33 in grade A (< 0.25) and 20 in grade B (0.25-1.00). Using a case-control study, simultaneously analyzed biomarkers associated with the severity and rate of progression of periodontitis. The red complex, the orange complex, Campylobacter spp., uncultured Candidatus Saccharibacteria and metabolites such as 5-Aminovaleric acid, N1-Acetylspermine showed a significant positive correlation with periodontal clinical parameters. Furthermore, we identified four of the salivary differential metabolites (DL-Leucineamide, Dodecanedioic acid, L-Tyrosine methyl ester and Phenylpyruvic acid) that may serve as potential biomarkers for predicting the rate of periodontitis progression. These results showed that the red complex significantly correlated with periodontitis severity and influenced changes in salivary metabolites. Additionally, biomarkers indicating the progression rate were predominantly amino acid derivatives, confirming that interactions between microorganisms and metabolites may exacerbate periodontitis development.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515495","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}

引用次数: 0

FDA-Approved Secukinumab Alleviates Glial Activation and Immune Cell Infiltration in MPTP-Induced Mouse Model of Parkinson's Disease.

IF 4.5 2区医学

Inflammation Pub Date : 2025-02-26 DOI: 10.1007/s10753-025-02267-8

Qi Li, Xiaoxuan Han, Mengmeng Dong, Lipeng Bai, Wei Zhang, Wei Liu, Fei Wang, Xiaodong Zhu

{"title":"FDA-Approved Secukinumab Alleviates Glial Activation and Immune Cell Infiltration in MPTP-Induced Mouse Model of Parkinson's Disease.","authors":"Qi Li, Xiaoxuan Han, Mengmeng Dong, Lipeng Bai, Wei Zhang, Wei Liu, Fei Wang, Xiaodong Zhu","doi":"10.1007/s10753-025-02267-8","DOIUrl":"https://doi.org/10.1007/s10753-025-02267-8","url":null,"abstract":"Interleukin-17A (IL-17A) has been implicated in the progression of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, the effect of the FDA-approved Secukinumab (SEC), an IL-17A inhibitor, on PD remains unclear. This study aimed to investigate the neuroprotective effect of SEC and its potential mechanisms in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Male C57BL/6 J mice were mainly assigned to three groups: Sham, MPTP, and MPTP + SEC. Motor coordination was assessed using the climbing rod and rotarod tests. Dopaminergic neurons (TH +) and glial cells (Iba-1 + , GFAP +) in the substantia nigra were evaluated using immunohistochemistry and immunofluorescence. Flow cytometry was used to analyze immune cell populations in the brain and spleen. Inflammatory cytokines and chemokines were quantified using RT-PCR. SEC treatment significantly alleviated the loss of dopaminergic neurons and improved motor coordination in MPTP mice. It also reduced the infiltration of peripheral immune cells, including CD4 + T cells, NK cells, and monocyte-macrophages into the brain. SEC attenuated glial activation (Iba-1 + , GFAP +) and decreased the expression of pro-inflammatory cytokines and chemokines (CCL2, CXCL9), which recruit immune cells into the brain. These results suggest that Secukinumab protects dopaminergic neurons and attenuates neuroinflammation in MPTP-induced model. SEC treatment in PD might be an effective therapeutic approach for clinical application in the future. HIGHLIGHTS: • Secukinumab reduces the loss of dopaminergic neurons and axons in MPTP mice. • Secukinumab inhibits the infiltration of peripheral immune cells into the brain in MPTP mice. • Secukinumab inhibits the activation of glial cells and reduces neuroinflammation in MPTP mice.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515493","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}

引用次数: 0

ZAKα Induces Pyroptosis of Colonic Epithelium Via the Caspase-11/GSDMD Pathway to Aggravate Colitis.

IF 4.5 2区医学

Inflammation Pub Date : 2025-02-24 DOI: 10.1007/s10753-025-02262-z

Song Li, Mingfei Chen, Sizhe Zheng, Waresi Abudourexiti, Feng Zhu, Zhongyuan Wang, Yanzhe Guo, Zeqian Yu, Zirui Yang, Liang Zhang, Chao Ding, Jianfeng Gong

{"title":"ZAKα Induces Pyroptosis of Colonic Epithelium Via the Caspase-11/GSDMD Pathway to Aggravate Colitis.","authors":"Song Li, Mingfei Chen, Sizhe Zheng, Waresi Abudourexiti, Feng Zhu, Zhongyuan Wang, Yanzhe Guo, Zeqian Yu, Zirui Yang, Liang Zhang, Chao Ding, Jianfeng Gong","doi":"10.1007/s10753-025-02262-z","DOIUrl":"https://doi.org/10.1007/s10753-025-02262-z","url":null,"abstract":"ZAKα-driven ribotoxic stress response (RSR) has been shown to trigger diverse biological effects. Nevertheless, its role in the pathogenesis of ulcerative colitis (UC) remained unclear. This study aimed to determine the role of ZAKα in the development of UC. Our study found that ZAKα expression was significantly increased in colonic epithelium of UC patients and DSS-colitis mouse models. Moreover, the expression level of ZAKα mRNA showed a positive correlation with disease activity. In the colitis model, Vemurafenib, the ZAKα inhibitor, treatment reduced colonic inflammation and ameliorated intestinal mucosal barrier damage, while Anisomycin, the RSR agonist, showed the opposite effect. In vitro experiments demonstrated that Anisomycin induced pyroptosis instead of apoptosis in C26 cell line. Western blot analysis revealed that Anisomycin triggered pyroptosis via the Caspase-11/GSDMD pathway. Further animal studies confirmed that Vemurafenib downregulated this pathway, reducing colonic epithelial cell pyroptosis. Finally, blocking Caspase-11 reduced severity of DSS-induced colitis in Anisomycin-treated mice. In all, ZAKα seems to play a crucial role in the pathogenesis of colitis, as it promotes pyroptosis in colonic epithelial cells and exacerbates colitis in part by upregulating the Caspase-11/GSDMD axis.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482875","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}

引用次数: 0

IRGM Inhibits the AKT/mTOR Signaling Pathway by Interacting with TRIM21 to Alleviate Sepsis-Induced Acute Lung Injury. IRGM 通过与 TRIM21 相互作用抑制 AKT/mTOR 信号通路，从而缓解败血症诱发的急性肺损伤。

IF 4.5 2区医学

Inflammation Pub Date : 2025-02-24 DOI: 10.1007/s10753-025-02265-w

Na Guo, Yu Xia, Nannan He, Lei Zhang, Jian Liu

{"title":"IRGM Inhibits the AKT/mTOR Signaling Pathway by Interacting with TRIM21 to Alleviate Sepsis-Induced Acute Lung Injury.","authors":"Na Guo, Yu Xia, Nannan He, Lei Zhang, Jian Liu","doi":"10.1007/s10753-025-02265-w","DOIUrl":"https://doi.org/10.1007/s10753-025-02265-w","url":null,"abstract":"Acute lung injury (ALI) is a severe complication of sepsis, and its underlying pathological mechanisms remain poorly understood. This study aims to investigate the role and mechanisms by which IRGM mediates autophagy through the regulation of the AKT/mTOR signaling pathway in sepsis-induced ALI. Initially, a sepsis-induced ALI mouse model was established using cecal ligation and puncture (CLP). Our results demonstrated that Irgm1 expression was significantly upregulated in the ALI model. Subsequently, Irgm1 was knocked down in vivo using AAV vectors, and changes in ALI symptoms were assessed. In vitro, a sepsis-induced ALI cell model was generated by stimulating A549 cells with lipopolysaccharide (LPS). The effects of IRGM overexpression on autophagy and apoptosis were evaluated, and its impact on the AKT/mTOR signaling pathway was analyzed. Furthermore, mass spectrometry and co-immunoprecipitation (COIP) experiments were conducted to explore the interaction between IRGM and TRIM21. In vivo results showed that Irgm1 knockout exacerbated CLP-induced ALI, as evidenced by a significant reduction in autophagic activity, increased apoptosis, and aberrant activation of the AKT/mTOR pathway. Further cellular experiments suggested that IRGM may enhance autophagy by inhibiting the AKT/mTOR signaling pathway, thereby attenuating LPS-induced cell damage. Additionally, COIP experiments revealed that IRGM interacts with TRIM21 to inhibit AKT/mTOR pathway activation, thereby promoting autophagy and mitigating sepsis-induced ALI. In conclusion, IRGM regulates autophagy through the AKT/mTOR signaling pathway and exerts protective effects in sepsis-induced ALI, suggesting that it may serve as a potential therapeutic target for sepsis-related ALI.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491900","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}

引用次数: 0