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

International Journal of Obesity (2025)Cite this article

Subjects

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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Fig. 1: Study design for two-sample Mendelian randomization (MR) analysis.
Fig. 2: MR analysis of inflammatory cytokines and T2D.
Fig. 3: Mouse model with T2D validation and cytokine profiling.
Fig. 4: scRNA-seq of PBMCs fromT2D and control mice.
Fig. 5: NK cell subpopulation analysis.
Fig. 6: CD4+ T cell subpopulation analysis.
Fig. 7: CD8+ T cell subpopulation analysis.
Fig. 8: B cell subpopulation analysis.
Fig. 9: Myeloid cell subpopulation analysis.
Fig. 10: Chemokine crosstalk between immune cells.

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Data availability

All sequence data for this study have been deposited in Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE274561.

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Acknowledgements

Yang Liu, Tao Wang and Rong Wu contributed equally to this work. Thanks to my Twelve-year-old daughter Qianshu Yao for her contribution in the mouse observation.

Funding

National Natural Science of China [No.31870886], National Science and Technology Major Project [2023ZD0509802], Natural Science Foundation of Zhejiang Province [No.LY22H050006], Medical Science and Technology Project of Zhejiang Province [No.2023KY324] and Huzhou Municipal Science and Technology Bureau [No.2023YZ52].

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Authors and Affiliations

  1. Huzhou Key Laboratory of Chronic Kidney Disease, First Affiliated Hospital, Huzhou University, Huzhou, China

    Yang Liu, Rong Wu, Lixia Huo, Xiaoyi Wang & Yunliang Yao

  2. School of Medicine & Nursing, Huzhou University, Huzhou, China

    Tao Wang, Jiapeng Gao, Jiexun Cai, Xiaoyu Li, Jingwen Li, Jue Wang, Zhen Wang & Yunliang Yao

  3. Hangzhou Linping Hospital of Traditional Chinese Medicine, Hangzhou, China

    Tao Wang

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Contributions

YL conceived the study and drafted the manuscript. TW and RW performed experiments and analyzed data. JG conducted bioinformatics analysis. JC established animal models. LH and XL performed data visualization and statistical analysis. JL and JW processed GWAS datasets. ZW helped write the manuscript. XW acquired funding and administered the project. YY supervised research and finalized the manuscript.

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Correspondence to Yunliang Yao.

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All animal procedures were approved by and performed according to guidelines of the Institutional Animal Care and Use Committee at the Huzhou University (IRB approval no.202203-27).

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Liu, Y., Wang, T., Wu, R. et al. Single-cell transcriptome atlas and genome-wide Mendelian randomization reveal chemokine involvement in diverse immune cells in type 2 diabetes. Int J Obes (2025). https://doi.org/10.1038/s41366-025-01846-x

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