Protectin D1/GPR37 Signaling Enhances Macrophage-Dependent Efferocytosis to Attenuate Experimental Abdominal Aortic Aneurysm Formation.

Abstract

Abdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disorder characterized by progressive aortic dilation and destruction of the vascular wall, often culminating in rupture. Current management is limited to surgical repair, with no approved targeted pharmacologic therapies. In this study, we investigated the immunomodulatory role of Protectin D1 (PD1), a specialized pro-resolving lipid mediator, through G-protein-coupled receptor 37 (GPR37) signaling on macrophages in mitigating AAA progression and preventing aortic rupture. Single-cell RNA sequencing analysis of human tissue demonstrated significant differences in PD1/GPR37 axis-related genes in macrophages in AAAs compared to control aortic tissue. Using an established murine AAA model, PD1 administration significantly attenuated aortic diameter, pro-inflammatory cytokine and matrix metalloproteinase (MMP2) expression, as well as maintained aortic morphology in a GPR37-dependent manner. Importantly, PD1 treatment prevented preformed AAA progression to aortic rupture in another preclinical elastase + BAPN model of aortic rupture by attenuating aortic diameter, tissue inflammation as well as decreasing macrophage infiltration, preserving elastin integrity, and restoring smooth muscle α-actin expression in the aortic wall. Mechanistically, PD1 enhanced macrophage efferocytosis of apoptotic vascular smooth muscle cells in the murine aortic tissue, as well as in isolated macrophages via GPR37-dependent manner and attenuated the inflammatory paracrine secretion of macrophage-specific paracrine release of TNF-α and IL-β. These findings suggest that PD1/GPR37 signaling on macrophages promotes inflammation-resolution by enhancing efferocytosis of apoptotic SMCs, conferring protection against aortic inflammation and remodeling to mitigate AAA formation and impending rupture.