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Background <p>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> Methods <p>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> Results <p>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> Conclusion <p>This work establishes a systems-level framework for chemokine signaling in T2D immunopathogenesis, identifying nodal regulators of immune crosstalk as potential therapeutic vulnerabilities.</p>

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

  • 期刊论文

  • 发表日期：

    2025年7月20日

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

摘要

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.