Macrophage LGR4-mediated signaling promotes cellular inflammation and exacerbates atherosclerosis 3882

Abstract Description Macrophages (M?s) play a key role in both initiation and progression of atherosclerosis. A recent study reported that leucine-rich repeat-containing G protein-coupled receptor (LGR) 4 regulates the proinflammatory phenotype of cardiac M?s. Our preliminary experiments demonstrated increased expression of LGR4 in human atherosclerotic aortic segments, identified Lgr4 as the major LGR isoform in primary murine M?s, and atherogenic oxLDL stimulated LGR4 expression in M?s. However, the role of M? LGR4 in atherogenesis remains unknown. We generated novel myeloid cell-specific Lgr4 knockout mice (Lgr4ΔM) by crossing Lgr4f/f and LysM Cre mice. AAV8-hPCSK9-injected Lgr4ΔM and control Lgr4fl/fl were fed a Western diet to investigate atherosclerosis. Male Lgr4ΔM mice exhibited reduced atherosclerosis and smaller necrotic cores compared with sex-matched Lgr4fl/fl controls, without any changes in circulating monocyte frequencies. Additionally, male Lgr4ΔM mice had decreased fat mass and blood glucose levels. Interestingly, no differences were observed among female mice. Further studies revealed reduced lipid accumulation, enhanced efferocytic capacity, a suppressed M1/M2 M? ratio, and attenuated expression of different LDL-uptake genes in Lgr4ΔM M?s. Moreover, Lgr4-deficient M?s showed diminished oxLDL uptake. Altogether, these findings suggest that myeloid cell Lgr4 contributes to atherosclerotic lesion formation and identify Lgr4 as a novel therapeutic target. Funding Sources This work was supported by the National Institutes of Health grants (K99HL146954 and 530 R00HL146954) and the UTHSC College of Pharmacy Research Seed Grant. Topic Categories Immune Mechanisms of Human Disease (HUM)