Journal of Clinical Investigation最新文献_第2页

A20's linear ubiquitin-binding motif restrains pathogenic activation of Th17 cells and IL-22-driven enteritis. A20的线性泛素结合基序抑制Th17细胞和il -22驱动的肠炎的致病性激活。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-09-02 DOI: 10.1172/JCI187499

Christopher J Bowman, Dorothea M Stibor, Xiaofei Sun, Nika Lenci, Hiromichi Shimizu, Emily F Yamashita, Rommel Advincula, Min Cheol Kim, Jessie A Turnbaugh, Yang Sun, Bahram Razani, Peter J Turnbaugh, Chun Jimmie Ye, Barbara A Malynn, Averil Ma

{"title":"A20's linear ubiquitin-binding motif restrains pathogenic activation of Th17 cells and IL-22-driven enteritis.","authors":"Christopher J Bowman, Dorothea M Stibor, Xiaofei Sun, Nika Lenci, Hiromichi Shimizu, Emily F Yamashita, Rommel Advincula, Min Cheol Kim, Jessie A Turnbaugh, Yang Sun, Bahram Razani, Peter J Turnbaugh, Chun Jimmie Ye, Barbara A Malynn, Averil Ma","doi":"10.1172/JCI187499","DOIUrl":"10.1172/JCI187499","url":null,"abstract":"A20, encoded by the TNFAIP3 gene, is a protein linked to Crohn's disease and celiac disease in humans. We now find that mice expressing point mutations in A20's M1-ubiquitin-binding zinc finger 7 (ZF7) motif spontaneously develop proximal enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveals expansion of Th17 cells and exuberant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7 mice. While deletion of IL-17A from A20ZF7/ZF7 mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. Colonization of adult germ-free mice with microbiota from adult WT specific pathogen-free mice drives duodenal IL-22 expression and duodenitis. A20ZF7/ZF7 Th17 cells autonomously express more RORγt and IL-22 after differentiation in vitro. ATAC sequencing identified an enhancer region upstream of the Il22 gene, and this enhancer demonstrated increased activating histone acetylation coupled with exaggerated Il22 transcription in A20ZF7/ZF7 T cells. Acute inhibition of RORγt normalized histone acetylation at this enhancer. Finally, CRISPR/Cas9-mediated ablation of A20ZF7 in human T cells increases RORγt expression and IL22 transcription. These studies link A20's M1-ubiquitin binding function with RORγt expression, expansion of Th17 cells, and epigenetic activation of IL-22-driven enteritis.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 17","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrated screening identifies GPR31 as a key driver and druggable target for metabolic dysfunction-associated steatohepatitis. 综合筛选确定GPR31是代谢功能障碍相关脂肪性肝炎的关键驱动因素和可药物靶点。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-09-02 DOI: 10.1172/JCI173193

Xiao-Jing Zhang, Jiajun Fu, Xu Cheng, Hong Shen, Hailong Yang, Kun Wang, Wei Li, Han Tian, Tian Tian, Junjie Zhou, Song Tian, Zhouxiang Wang, Juan Wan, Lan Bai, Hongfei Duan, Xin Zhang, Ruifeng Tian, Haibo Xu, Rufang Liao, Toujun Zou, Jing Shi, Weiyi Qu, Liang Fang, Jingjing Cai, Peng Zhang, Zhi-Gang She, Jingwei Jiang, Yufeng Hu, Yibin Wang, Hongliang Li

{"title":"Integrated screening identifies GPR31 as a key driver and druggable target for metabolic dysfunction-associated steatohepatitis.","authors":"Xiao-Jing Zhang, Jiajun Fu, Xu Cheng, Hong Shen, Hailong Yang, Kun Wang, Wei Li, Han Tian, Tian Tian, Junjie Zhou, Song Tian, Zhouxiang Wang, Juan Wan, Lan Bai, Hongfei Duan, Xin Zhang, Ruifeng Tian, Haibo Xu, Rufang Liao, Toujun Zou, Jing Shi, Weiyi Qu, Liang Fang, Jingjing Cai, Peng Zhang, Zhi-Gang She, Jingwei Jiang, Yufeng Hu, Yibin Wang, Hongliang Li","doi":"10.1172/JCI173193","DOIUrl":"10.1172/JCI173193","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH) is a globally prevalent but intractable disease lacking effective pharmacotherapies. Here, we performed an integrated multilayered screening for pathogenic genes and druggable targets for MASH. We identified the subclass of metabolite-sensing G protein-coupled receptors, specifically GPR31, a critical contributor to MASH occurrence, which, to our knowledge, was previously uncharacterized. Mechanistically, Gαi3 is the essential downstream effector for the pro-MASH efficiency of GPR31 via glycosylation-dependent interaction with GPR31 and extra activation of PKCδ-MAPK signaling. Hepatocyte-specific GPR31 deficiency robustly blocked hepatic lipotoxicity and fibrosis in a mouse model of diet-induced MASH, whereas expression of the GPR31 transgene aggravated MASH development. Of translational importance, we developed a small-molecule inhibitor, named G4451, that specifically inhibits the GPR31-Gαi3 interaction by targeting the GPR31 conformational transition. Encouragingly, oral administration of G4451 effectively blocked MASH progression in preclinical models in both rodents and nonhuman primates. Collectively, the present study provides proof of concept that interference with GPR31 constitutes an attractive therapeutic strategy for MASH.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 17","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MPO-anchored ENO1 mediates neutrophil extracellular trap DNA for enhancing Treg differentiation via IFITM2 during sepsis. mpo锚定的ENO1介导中性粒细胞胞外陷阱DNA，通过IFITM2在败血症期间增强Treg分化。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-09-02 DOI: 10.1172/JCI183541

Yi Jiang, Shenjia Gao, Xiya Li, Hao Sun, Xinyi Wu, Jiahui Gu, Zhaoyuan Chen, Han Wu, Xiaoqiang Zhao, Tongtong Zhang, Ronen Ben-Ami, Yuan Le, Timothy R Billiar, Changhong Miao, Jie Zhang, Jun Wang, Wankun Chen

{"title":"MPO-anchored ENO1 mediates neutrophil extracellular trap DNA for enhancing Treg differentiation via IFITM2 during sepsis.","authors":"Yi Jiang, Shenjia Gao, Xiya Li, Hao Sun, Xinyi Wu, Jiahui Gu, Zhaoyuan Chen, Han Wu, Xiaoqiang Zhao, Tongtong Zhang, Ronen Ben-Ami, Yuan Le, Timothy R Billiar, Changhong Miao, Jie Zhang, Jun Wang, Wankun Chen","doi":"10.1172/JCI183541","DOIUrl":"https://doi.org/10.1172/JCI183541","url":null,"abstract":"Sepsis is a life-threatening disease caused by a dysfunctional host response to infection. During sepsis, inflammation-related immunosuppression is the critical factor causing secondary infection and multiple organ dysfunction syndrome. The regulatory mechanisms underlying regulatory T-cell (Treg) differentiation and function, which significantly contribute to septic immunosuppression, require further clarification. In this study, we found that neutrophil extracellular traps (NETs) participated in the development of sepsis-induced immunosuppression by enhancing Treg differentiation and function via direct interaction with CD4+ T cells. Briefly, NETs anchored enolase 1 (ENO1) on the membrane of CD4+ T cells through its key protein myeloperoxidase (MPO) and subsequently recruited interferon-induced transmembrane protein 2 (IFITM2). IFITM2 acted as a DNA receptor that sensed NETs-DNA and activated intracellular RAS-associated protein 1B (RAP1B) and its downstream extracellular signal-regulated kinase (ERK) signaling pathway to promote Treg differentiation and function. ENO1 inhibition significantly attenuated NETs-induced Treg differentiation and alleviated sepsis in mice. Overall, we demonstrated the role of NETs in sepsis-induced immunosuppression by enhancing Treg differentiation, identified ENO1 as an anchor of NETs-MPO, and elucidated the downstream molecular mechanism by which IFITM2-RAP1B-ERK regulated Treg differentiation. These findings improve our understanding of the immunopathogenesis of sepsis and provide potential therapeutic targets for sepsis-induced immunosuppression.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Corrigendum to Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells. 缺氧抑制双特异性磷酸酶-2可增加人类癌细胞的化疗耐药和恶性肿瘤。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-09-02 DOI: 10.1172/JCI198108

Shih-Chieh Lin, Chun-Wei Chien, Jenq-Chang Lee, Yi-Chun Yeh, Keng-Fu Hsu, Yen-Yu Lai, Shao-Chieh Lin, Shaw-Jenq Tsai

引用次数: 0

Maladaptive trained immunity in viral infections. 病毒感染中的适应性训练免疫不良。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-09-02 DOI: 10.1172/JCI192469

Dmitri Sviridov, Mihai G Netea, Michael I Bukrinsky

{"title":"Maladaptive trained immunity in viral infections.","authors":"Dmitri Sviridov, Mihai G Netea, Michael I Bukrinsky","doi":"10.1172/JCI192469","DOIUrl":"10.1172/JCI192469","url":null,"abstract":"Trained immunity (TRIM) is a form of long-lasting functional reprogramming of innate immune cells and their progenitors that enhances responsiveness to subsequent stimuli. Although first characterized in myeloid cells, TRIM was recently extended to nonmyeloid cell types, including endothelial and glial cells, which also exhibit stimulus-driven, memory-like behavior. While initially recognized as a protective mechanism, particularly in the context of vaccines and acute infections, TRIM can also become maladaptive, promoting chronic inflammation, immune dysfunction, and disease. This Review focuses on virus-induced TRIM while also addressing microbial, metabolic, and endogenous inducers. We examine key ligands and receptors that initiate TRIM and dissect the associated signaling and epigenetic pathways. Importantly, we argue that maladaptive TRIM arises not from a specific ligand, receptor, or molecular event, but from contextual factors such as stimulus persistence, dose, tissue microenvironment, and preexisting inflammation. The nature of the secondary challenge also shapes whether a trained response is adaptive or maladaptive. We further discuss TRIM induction in the bone marrow, involvement of both myeloid and nonmyeloid cells, and the role of lipid rafts in sustaining TRIM. We review maladaptive TRIM's potential contribution to systemic diseases, such as atherosclerosis, diabetes, sepsis, cancer, and autoimmunity, along with its influence on viral vaccine responses. Finally, we outline potential strategies to redirect maladaptive TRIM and propose key outstanding questions for future research.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 17","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unraveling endocannabinoid signaling disruption in a preclinical model of neurodevelopmental disorders. 在神经发育障碍的临床前模型中揭示内源性大麻素信号中断。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-09-02 DOI: 10.1172/JCI196707

Nephi Stella

引用次数: 0

Corrigendum to SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria. SLAMF7和SLAMF8受体的勘误表塑造人浆细胞样树突状细胞对细胞内细菌的反应。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-09-02 DOI: 10.1172/JCI198064

Joaquín Miguel Pellegrini, Anne Keriel, Laurent Gorvel, Sean Hanniffy, Vilma Arce-Gorvel, Mile Bosilkovski, Javier Solera, Stéphane Méresse, Sylvie Mémet, Jean-Pierre Gorvel

引用次数: 0

Microbiota in interstitial cystitis/bladder pain syndrome: evidence and opportunities. 间质性膀胱炎/膀胱疼痛综合征的微生物群：证据和机会。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-09-02 DOI: 10.1172/JCI197858

David J Klumpp

引用次数: 0

IGFBP6 orchestrates anti-infective immune collapse in murine sepsis via prohibitin-2-mediated immunosuppression. IGFBP6通过禁止素-2介导的免疫抑制，协调小鼠败血症的抗感染免疫崩溃。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-09-02 DOI: 10.1172/JCI184721

Kai Chen, Ying Hu, Xiaoyan Yu, Hong Tang, Yanting Ruan, Yue Li, Xun Gao, Qing Zhao, Hong Wang, Xuemei Zhang, David Paul Molloy, Yibing Yin, Dapeng Chen, Zhixin Song

{"title":"IGFBP6 orchestrates anti-infective immune collapse in murine sepsis via prohibitin-2-mediated immunosuppression.","authors":"Kai Chen, Ying Hu, Xiaoyan Yu, Hong Tang, Yanting Ruan, Yue Li, Xun Gao, Qing Zhao, Hong Wang, Xuemei Zhang, David Paul Molloy, Yibing Yin, Dapeng Chen, Zhixin Song","doi":"10.1172/JCI184721","DOIUrl":"https://doi.org/10.1172/JCI184721","url":null,"abstract":"The persistent challenge of sepsis-related mortality underscores the necessity for deeper insights, with our multi-center cross-age cohort study identifying insulin-like growth factor binding protein 6 (IGFBP6) as a critical regulator in sepsis diagnosis, prognosis, and mortality risk evaluation. Mechanistically, IGFBP6 engages in IGF-independent binding to prohibitin2 (PHB2) on epithelial cells, driving PHB2 tyrosine phosphorylation during sepsis. This process disrupts STAT1 phosphorylation, nuclear translocation, and its recruitment to the CCL2 promoter, ultimately impairing CCL2 transcription and macrophage chemotaxis. Crucially, PHB2 silencing via siPHB2 and STAT1 activation using 2-NP restored CCL2 expression in vitro and in vivo, improving bacterial clearance and survival in septic mice. Concurrently, IGFBP6 compromises macrophage bactericidal activity by inhibiting Akt phosphorylation, reducing ROS/IL-1β production and phagocytic capacity - defects reversible by Akt agonist SC79. Collectively, IGFBP6 emerges as an endogenous driver of sepsis pathogenesis, positioning it as a dual diagnostic biomarker and therapeutic target. Intervention strategies targeting IGFBP6-mediated signaling may offer transformative approaches for sepsis management.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Intermittent ischemia-reperfusion as a potent insulin-sensitizing intervention via blood flow enhancement and muscle Decanoyl-L-carnitine suppression. 间歇性缺血-再灌注作为一种有效的胰岛素增敏干预，通过血流增强和肌肉decanoyl - l-肉碱抑制。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-09-02 DOI: 10.1172/JCI183567

Kohei Kido, Janne R Hingst, Johan Onslev, Kim A Sjøberg, Jesper B Birk, Nicolas O Eskesen, Tongzhu Zhou, Kentaro Kawanaka, Jesper F Havelund, Nils J Færgeman, Ylva Hellsten, Jørgen F P Wojtaszewski, Rasmus Kjøbsted

{"title":"Intermittent ischemia-reperfusion as a potent insulin-sensitizing intervention via blood flow enhancement and muscle Decanoyl-L-carnitine suppression.","authors":"Kohei Kido, Janne R Hingst, Johan Onslev, Kim A Sjøberg, Jesper B Birk, Nicolas O Eskesen, Tongzhu Zhou, Kentaro Kawanaka, Jesper F Havelund, Nils J Færgeman, Ylva Hellsten, Jørgen F P Wojtaszewski, Rasmus Kjøbsted","doi":"10.1172/JCI183567","DOIUrl":"10.1172/JCI183567","url":null,"abstract":"A single bout of exercise improves muscle insulin sensitivity for up to 48 hours via the AMP-activated protein kinase (AMPK). Limb ischemia activates AMPK in muscle, and subsequent reperfusion enhances insulin-stimulated vasodilation, potentially eliciting a more pronounced exercise effect with reduced workload. Here, we investigated the combined effect of upper leg intermittent ischemia-reperfusion (IIR) and continuous knee-extension exercise on muscle insulin sensitivity regulation. We found that IIR-exercise potentiated AMPK activation and muscle insulin sensitivity. The potentiating effect of IIR-exercise on muscle insulin sensitivity was associated with increased insulin-stimulated blood flow in parallel with enhanced phosphorylation of endothelial nitric oxide synthase. Metabolomics analyses demonstrated a suppression of muscle medium-chain acylcarnitines during IIR-exercise, which correlated with insulin sensitivity and was consistent with findings in isolated rat muscle treated with Decanoyl-L-carnitine. Collectively, combining IIR with low-to-moderate intensity exercise may represent a promising intervention to effectively enhance muscle insulin sensitivity. This approach could offer potential for mitigating muscle insulin resistance in clinical settings and among individuals with lower physical activity levels.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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