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

Highlights

• BDNF is low-expressed in DMAS patients.

• Over-expression of BDNF alleviates AS in DM mice.

• Restoration of BDNF inhibits the STAT3 pathway.

• BDNF promotes M2 polarization of macrophages by inhabiting STAT3 pathway.

• Over-expressed BDNF delays the progression of AS in LDLR^−/− mice with DMAS.

Abstract

Diabetes mellitus-accelerated atherosclerosis (DMAS) is one of the vascular complications of diabetes. Brain-derived 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 expression of inflammatory cytokines (IL-1β, TNF-α, IL-10, TGF-β 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-1β and TNF-α, and increased IL-10, TGF-β 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.

Introduction

Diabetes mellitus (DM) represents one of the main risk factors in the development of cardiovascular disease and both type 1 and type 2 diabetes are correlated with accelerated atherosclerosis (AS) [1]. The current therapies for atherosclerotic cardiovascular disease in type 2 diabetic patients are mainly focused on optimal glycemic control through medication and other various approaches [2]. Tissue inflammation is a classical characteristic of obesity, type 2 diabetes and other insulin-resistant states, and the dominant immune cell type causing inflammation in obese and type 2 diabetes islets is the macrophage [3]. Macrophages are classified into classically (M1) and alternatively (M2) activated cells [4]. Macrophage activation generally promotes the progression of chronic inflammatory diseases and both M1 and M2 monocytes can produce pro-inflammatory cytokines (such as interleukin (IL)-1 and tumor necrosis factor (TNF) [5]. Macrophages are associated with type 2 DM [6]. The effects of brain-derived neurotrophic factor (BDNF) on type 2 diabetes have been explored [7]. However, to our knowledge, the role of BDNF in the progression of DMAS remains unclear.

BDNF is positively correlated with differentiation, activity-dependent plasticity, and survival of neurons in the central nervous system [8]. Patients with type 2 diabetes have decreased levels of BDNF in their cerebral output and plasma [9]. Signal transducer and activator of transcription 3 (STAT3) is involved in inflammation and cellular transformation [10]. Suppression of the STAT3 pathway eliminates the protective effect of Humanin, which consequently represses/prevents the initiation of diabetes in non-obese DM mice [11]. Another study has shown that the STATs pathway promotes the progression of skeletal muscle insulin resistance in patients with type 2 diabetes [12]. Therefore, it was hypothesized that BDNF and the STAT3 pathway were involved in DMAS. This study investigated the mechanism by which BDNF influences macrophage differentiation and the interaction between the STAT3 pathway the development of DMAS in hopes of identifying potential targets in the treatment of DMAS.