Hematopoietic dipeptidyl peptidase-4 deficiency promotes M2 macrophage polarization and attenuates atherosclerosis

Atherosclerosis is a chronic inflammatory disease wherein macrophage polarization critically influences lesion development. Dipeptidyl peptidase-4 (DPP4), a serine protease expressed on immune cells, has been implicated in vascular inflammation; however, its cell type-specific roles remain unclear. This study aimed to determine whether Dpp4 deficiency, particularly in hematopoietic cells, affects macrophage polarization and atherosclerosis progression. Using Apoe-knockout (ApoeKO) and Apoe- and Dpp4-double knockout mice as well as bone marrow transplantation models, we evaluated the impact of systemic and myeloid-specific Dpp4 deficiency on macrophage phenotype and atherogenesis. In bone marrow-derived macrophages, Dpp4 deficiency enhanced M2 marker expression (Arg1, Ym1, Mgl2, and Fizz1) and increased the proportion of CD206⁺ M2 macrophages without affecting M1 polarization, particularly after interleukin (IL)-4 stimulation. Furthermore, in vivo Dpp4 deficiency significantly reduced aortic lesion area and macrophage infiltration in ApoeKO mice. Real-time reverse transcription-polymerase chain reaction analysis of aortic tissue revealed upregulation of M2-related genes and Il4 expression, while M1-associated markers remained unchanged. Bone marrow transplantation experiments demonstrated that hematopoietic Dpp4 deficiency was sufficient to suppress atherosclerosis, independent of systemic glucose or lipid alterations. This protective effect was accompanied by enhanced M2 polarization, suggesting a role for DPP4 in regulating macrophage phenotype. Collectively, these findings identify hematopoietic DPP4 as a key modulator of macrophage polarization and atherogenesis. Dpp4 deficiency promotes the anti-inflammatory M2 phenotype and attenuates atherosclerosis regardless of metabolic effects, indicating that DPP4 may represent a promising therapeutic target for inflammatory cardiovascular diseases.