Macrophage A2aR Alleviates LPS-Induced Vascular Endothelial Injury and Inflammation via Inhibiting M1 Polarisation and Oxidative Stress

Abstract

Vascular inflammation and endothelial dysfunction secondary to unchecked activation of endothelium are key mechanisms underlying sepsis and organ failure. However, the intrinsic processes that mitigate excessive endothelial cell activation remain incompletely understood. To determine the central role of adenosine A2a receptor (A2aR) on macrophages in modulating lipopolysaccharide (LPS)-induced vascular endothelial dysfunction, we constructed macrophage A2aR-conditional knockout (Mac-A2aR KO) mice, and stimulated the mice and macrophages with LPS. A2aR agonist, CGS21680, was administered to these models to further explore its impact. Results showed that knockout of Macrophage A2aR exacerbated LPS-induced vascular permeability, oedema, inflammatory cardiac damage and upregulated expression of intercellular adhesion molecule-1 (ICAM-1) and E-selectin in cardiopulmonary vascular endothelium. Moreover, deletion of A2aR on macrophages also markedly aggravated LPS-induced increases in reactive oxygen species (ROS) and declines in antioxidant enzyme gene mRNA and protein expression levels related to oxidative stress (OS). Furthermore, deficiency of A2aR in bone marrow-derived macrophages (BMDMs) promotes LPS-induced macrophage M1 polarisation and secretion of inflammatory cytokines, especially tumour necrosis factor-alpha (TNF-α). Conversely, the pretreatment with CGS21680 in vivo and in vitro showed corresponding improvement in functions of vascular endothelial dysfunction. These data demonstrate that A2aR in macrophages represents a promising novel therapeutic target for LPS-induced uncontrolled vascular endothelial injury and inflammation potentially through reducing macrophage M1 polarisation and OS and inhibiting the production and release of TNF-α production.