Yang Liu, Tao Wang, Rong Wu, Jiapeng Gao, Jiexun Cai, Lixia Huo, Xiaoyu Li, Jingwen Li, Jue Wang, Zhen Wang, Xiaoyi Wang, Yunliang Yao
{"title":"单细胞转录组图谱和全基因组孟德尔随机化揭示趋化因子参与2型糖尿病多种免疫细胞。","authors":"Yang Liu, Tao Wang, Rong Wu, Jiapeng Gao, Jiexun Cai, Lixia Huo, Xiaoyu Li, Jingwen Li, Jue Wang, Zhen Wang, Xiaoyi Wang, Yunliang Yao","doi":"10.1038/s41366-025-01846-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Chemokine-driven immune dysregulation is increasingly recognized as a hallmark of T2D pathogenesis(T2D), where insulin resistance and metabolic stressors drive chronic inflammation. While chemokine cascades are hypothesized to mediate diabetic immunopathology, causal mediators remain undefined.</p><p><strong>Methods: </strong>We employed Mendelian Randomization (MR) of genome-wide association studies to identify causal inflammatory mediators, serological validation in streptozotocin-induced murine T2D models, and single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMC) to map immune cell heterogeneity and intercellular communication networks.</p><p><strong>Results: </strong>MR prioritized IFN-γ, CCL7, MIF, and CXCL9 as genetically supported T2D effectors. Murine validation confirmed CCL7 and MIF as robust circulating mediators. scRNA-seq revealed compartment-specific chemokine receptor dynamics (CCR4/5/6, CXCR3/4/5, CX3CR1), dominated by enhanced CCL5-CCR5 and CCL6-CCR2 crosstalk.</p><p><strong>Conclusion: </strong>This work establishes a systems-level framework for chemokine signaling in T2D immunopathogenesis, identifying nodal regulators of immune crosstalk as potential therapeutic vulnerabilities.</p>","PeriodicalId":14183,"journal":{"name":"International Journal of Obesity","volume":" ","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Single-cell transcriptome atlas and genome-wide Mendelian randomization reveal chemokine involvement in diverse immune cells in type 2 diabetes.\",\"authors\":\"Yang Liu, Tao Wang, Rong Wu, Jiapeng Gao, Jiexun Cai, Lixia Huo, Xiaoyu Li, Jingwen Li, Jue Wang, Zhen Wang, Xiaoyi Wang, Yunliang Yao\",\"doi\":\"10.1038/s41366-025-01846-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Chemokine-driven immune dysregulation is increasingly recognized as a hallmark of T2D pathogenesis(T2D), where insulin resistance and metabolic stressors drive chronic inflammation. While chemokine cascades are hypothesized to mediate diabetic immunopathology, causal mediators remain undefined.</p><p><strong>Methods: </strong>We employed Mendelian Randomization (MR) of genome-wide association studies to identify causal inflammatory mediators, serological validation in streptozotocin-induced murine T2D models, and single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMC) to map immune cell heterogeneity and intercellular communication networks.</p><p><strong>Results: </strong>MR prioritized IFN-γ, CCL7, MIF, and CXCL9 as genetically supported T2D effectors. Murine validation confirmed CCL7 and MIF as robust circulating mediators. scRNA-seq revealed compartment-specific chemokine receptor dynamics (CCR4/5/6, CXCR3/4/5, CX3CR1), dominated by enhanced CCL5-CCR5 and CCL6-CCR2 crosstalk.</p><p><strong>Conclusion: </strong>This work establishes a systems-level framework for chemokine signaling in T2D immunopathogenesis, identifying nodal regulators of immune crosstalk as potential therapeutic vulnerabilities.</p>\",\"PeriodicalId\":14183,\"journal\":{\"name\":\"International Journal of Obesity\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2025-07-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Obesity\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41366-025-01846-x\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Obesity","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41366-025-01846-x","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Single-cell transcriptome atlas and genome-wide Mendelian randomization reveal chemokine involvement in diverse immune cells in type 2 diabetes.
Background: Chemokine-driven immune dysregulation is increasingly recognized as a hallmark of T2D pathogenesis(T2D), where insulin resistance and metabolic stressors drive chronic inflammation. While chemokine cascades are hypothesized to mediate diabetic immunopathology, causal mediators remain undefined.
Methods: We employed Mendelian Randomization (MR) of genome-wide association studies to identify causal inflammatory mediators, serological validation in streptozotocin-induced murine T2D models, and single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMC) to map immune cell heterogeneity and intercellular communication networks.
Results: MR prioritized IFN-γ, CCL7, MIF, and CXCL9 as genetically supported T2D effectors. Murine validation confirmed CCL7 and MIF as robust circulating mediators. scRNA-seq revealed compartment-specific chemokine receptor dynamics (CCR4/5/6, CXCR3/4/5, CX3CR1), dominated by enhanced CCL5-CCR5 and CCL6-CCR2 crosstalk.
Conclusion: This work establishes a systems-level framework for chemokine signaling in T2D immunopathogenesis, identifying nodal regulators of immune crosstalk as potential therapeutic vulnerabilities.
期刊介绍：
The International Journal of Obesity is a multi-disciplinary forum for research describing basic, clinical and applied studies in biochemistry, physiology, genetics and nutrition, molecular, metabolic, psychological and epidemiological aspects of obesity and related disorders.
We publish a range of content types including original research articles, technical reports, reviews, correspondence and brief communications that elaborate on significant advances in the field and cover topical issues.
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