Brain-derived neurotrophic factor alleviates diabetes mellitus-accelerated atherosclerosis by promoting M2 polarization of macrophages through repressing the STAT3 pathway

Diabetes mellitus-accelerated atherosclerosis (DMAS) is one of the vascular complications of diabetes. Brainderived neurotrophic factor (BDNF) plays a critical role in diabetes mellitus. However, the mechanism by which BDNF is involved in DMAS remains unknown. This study investigates the effect of BDNF on the progression of DMAS as well as the underlying mechanism of action. The levels of BDNF in serum and peripheral blood mononuclear cells (PBMCs) from patients with DMAS and health controls were measured as well as the ex- pression of inflammatory cytokines (IL-1 beta, TNF-alpha, IL-10, TGF-beta and IL-13). The effects of BDNF restoration on cytokine release, macrophage differentiation and the formation of atherosclerotic plaques were evaluated both in vitro and in vivo using the DMAS mouse model. Downregulation of BDNF was identified in the serum and PBMCs of patients with DMAS. Elevation of BDNF contributed to a reduction in the AS lesion area in low-density lipoprotein receptor(-/-) mice, inactivated the STAT3 pathway, decreased pro-inflammatory cytokines IL-1 beta and TNF-alpha, and increased IL-10, TGF-beta and IL-13. BDNF overexpression also increased the proportion of M2 macrophages and alleviated atherosclerotic lesions. Our findings demonstrate that BDNF overexpression promotes M2 macrophage polarization, which represses the development of DMAS by inactivating the STAT3 pathway.