Liu Yang, Wang Tao, Wu Rong, Gao Jiapeng, Cai Jiexun, Huo Lixia, Li Xiaoyu, Li Jingwen, Wang Jue, Wang Zhen, Wang Xiaoyi, Yao Yunliang
Huzhou Key Laboratory of Chronic Kidney Disease, First Affiliated Hospital, Huzhou University, Huzhou, China.
School of Medicine & Nursing, Huzhou University, Huzhou, China.
Int J Obes (Lond). 2025 Jul 20. doi: 10.1038/s41366-025-01846-x.
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.
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.
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.
This work establishes a systems-level framework for chemokine signaling in T2D immunopathogenesis, identifying nodal regulators of immune crosstalk as potential therapeutic vulnerabilities.
趋化因子驱动的免疫失调日益被认为是2型糖尿病（T2D）发病机制的一个标志，其中胰岛素抵抗和代谢应激源会引发慢性炎症。虽然推测趋化因子级联反应介导糖尿病免疫病理学，但因果介质仍不明确。
我们采用全基因组关联研究的孟德尔随机化（MR）来确定因果性炎症介质，在链脲佐菌素诱导的小鼠T2D模型中进行血清学验证，并对外周血单核细胞（PBMC）进行单细胞RNA测序（scRNA-seq）以绘制免疫细胞异质性和细胞间通信网络。
MR将干扰素-γ、CCL7、巨噬细胞移动抑制因子（MIF）和CXCL9列为有遗传学依据的T2D效应因子。小鼠验证证实CCL7和MIF是强大的循环介质。scRNA-seq揭示了特定区室的趋化因子受体动态变化（CCR4/5/6、CXCR3/4/5、CX3CR1），主要表现为CCL5-CCR轴和CCL6-CCR2串扰增强。
这项工作建立了一个T2D免疫发病机制中趋化因子信号传导的系统水平框架，确定免疫串扰的节点调节因子为潜在的治疗靶点。
