Single-cell transcriptome atlas and genome-wide Mendelian randomization reveal chemokine involvement in diverse immune cells in type 2 diabetes.

IF 3.8 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

International Journal of Obesity Pub Date : 2025-07-20 DOI:10.1038/s41366-025-01846-x

Yang Liu, Tao Wang, Rong Wu, Jiapeng Gao, Jiexun Cai, Lixia Huo, Xiaoyu Li, Jingwen Li, Jue Wang, Zhen Wang, Xiaoyi Wang, Yunliang Yao

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引用次数: 0

Abstract

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.

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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。

背景：趋化因子驱动的免疫失调越来越被认为是T2D发病机制（T2D）的标志，其中胰岛素抵抗和代谢应激源驱动慢性炎症。虽然趋化因子级联被假设介导糖尿病免疫病理，但因果介质仍不明确。方法：我们采用全基因组关联研究的孟德尔随机化（MR）来确定因果炎症介质，在链脲霉素诱导的小鼠T2D模型中进行血清学验证，并对外周血单个核细胞（PBMC）进行单细胞RNA测序（scRNA-seq）来绘制免疫细胞异质性和细胞间通讯网络。结果：MR优先考虑IFN-γ、CCL7、MIF和CXCL9作为基因支持的T2D效应物。小鼠验证证实CCL7和MIF是稳健的循环介质。scRNA-seq揭示了室特异性趋化因子受体动力学（CCR4/5/6、CXCR3/4/5、CX3CR1），以CCL5-CCR5和CCL6-CCR2串扰增强为主。结论：本工作建立了T2D免疫发病机制中趋化因子信号传导的系统水平框架，确定了免疫串扰的节点调节因子作为潜在的治疗脆弱性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Obesity 医学-内分泌学与代谢

CiteScore

10.00

自引率

2.00%

发文量

221

审稿时长

3 months

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.