Mapping Endothelial-Macrophage Interactions in Diabetic Vasculature: Role of TREM2 in Vascular Inflammation and Ischemic Response.

Vasculopathies occur 15 years earlier in individuals with diabetes mellitus (DM) as compared to those without, but the underlying mechanisms driving diabetic vasculopathy remain incompletely understood. Endothelial cells (ECs) and macrophages (MΦ) are critical players in vascular wall and their crosstalk is crucial in diabetic vasculopathy. In diabetes, EC activation enables monocyte recruitment, which transmigrate into the intima and differentiate into macrophages (MΦ). Beyond this established model of diapedesis, EC-MΦ interplay is highly intricate and heterogenous. To capture these highly context dependent EC-MΦ interactions, we leveraged single-cell (sc)RNA-seq in conjunction with spatial transcriptome (ST)-seq profiling to analyze human mesenteric arteries from non-diabetic (ND) and type 2 diabetic (T2D) donors. We provide in this study a transcriptomic map encompassing major arterial vascular cells, e.g., EC, mononuclear phagocyte (MP), and T cells, and their interactions associated with human T2D. Furthermore, we identified Triggering Receptor Expressed on Myeloid Cells 2 ( TREM2) as a top T2D-induced gene in MP, with concomitant increase of TREM2 ligands in ECs. TREM2 induction was confirmed in mouse models of T2D and monocyte/MΦ subjected to DM-mimicking stimuli. Perturbing TREM2 with either an antibody or silencing RNA in MPs led to decreased pro-inflammatory responses in MPs and ECs and increased EC migration in vitro . In a mouse model of diabetes, TREM2 expression and its interaction with ECs are increased in the ischemic, as compared to non-ischemic muscles. Importantly, neutralization of TREM2 using a neutralizing antibody enhanced ischemic recovery and flow reperfusion in the diabetic mice, suggesting a role of TREM2 in promoting diabetic PAD. Finally, we verified that both TREM2 expression and the TREM2-EC-interaction are increased in human patients with DM-PAD. Collectively, our study presents the first atlas of human diabetic vessels with a focus on EC-MP interactions. Exemplified by TREM2, our study provides valuable insights into EC-MΦ interactions, key processes contributing to diabetic vasculopathies and the potential of targeting these interactions for therapeutic development.