Dipeptidyl Peptidase 4/Midline-1 Axis Promotes T Lymphocyte Motility in Atherosclerosis.
Dipeptidyl Peptidase 4/Midline-1 Axis Promotes T Lymphocyte Motility in Atherosclerosis.
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DOI：
10.1002/advs.202204194
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发表时间：
2023-03
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T细胞在动脉粥样硬化中起着至关重要的作用，其浸润先于动脉粥样硬化形成。然而，T细胞浸润在动脉粥样硬化中如何调节仍然在很大程度上未知。在这里，这项工作表明，二肽基肽酶-4（DPP 4）是动脉粥样硬化中T细胞运动的一种新型调节剂。单细胞核糖核酸（RNA）测序和流式细胞术显示，动脉粥样硬化患者的CD 4 + T细胞显示出DPP 4的显著增加。在动脉粥样硬化小鼠模型中，造血细胞或T细胞中缺乏DPP 4减少了T细胞浸润和动脉粥样硬化斑块体积。从机制上讲，DPP 4缺乏通过抑制T细胞中微管相关蛋白中线-1（Mid 1）的表达来降低T细胞运动性。DPP 4或Mid 1的缺失抑制趋化因子诱导的形状变化和运动性，而Dpp 4 −/− T细胞中Mid 1的恢复在很大程度上恢复了其迁移能力。因此，DPP 4/Mid 1作为一种新的T细胞运动调节因子，可能是动脉粥样硬化的潜在炎症靶点。本文报道了一种调节T细胞浸润动脉粥样硬化斑块的新机制。二肽基肽酶4（DPP 4）被鉴定为通过中线1依赖性细胞骨架重排促进动脉粥样硬化中T细胞迁移的关键分子。DPP 4的非酶功能可能成为动脉粥样硬化疾病的潜在治疗靶点。
T cells play a crucial role in atherosclerosis, with its infiltration preceding the formation of atheroma. However, how T‐cell infiltration is regulated in atherosclerosis remains largely unknown. Here, this work demonstrates that dipeptidyl peptidase‐4 (DPP4) is a novel regulator of T‐cell motility in atherosclerosis. Single‐cell ribonucleic acid (RNA) sequencing and flow cytometry show that CD4+ T cells in atherosclerotic patients display a marked increase of DPP4. Lack of DPP4 in hematopoietic cells or T cells reduces T‐cell infiltration and atherosclerotic plaque volume in atherosclerosis mouse models. Mechanistically, DPP4 deficiency reduces T‐cell motility by suppressing the expression of microtubule associated protein midline‐1 (Mid1) in T cells. Deletion of either DPP4 or Mid1 inhibits chemokine‐induced shape change and motility, while restitution of Mid1 in Dpp4−/− T cell largely restores its migratory ability. Thus, DPP4/Mid1, as a novel regulator of T‐cell motility, may be a potential inflammatory target in atherosclerosis. A novel mechanism regulating T‐cell infiltration into atherosclerotic plaque is reported here. Dipeptidyl peptidase 4 (DPP4) is identified as a crucial molecule promoting T‐cell migration in atherosclerosis via midline‐1‐dependent cytoskeletal rearrangement. The nonenzymatic function of DPP4 may serve as a potential therapeutic target for atherosclerotic disease.
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