Abstract 502: Trem2 Regulates Foamy Macrophage Formation In Atherosclerotic Plaque Formation

Atherosclerosis is driven by the accumulation of lipid in artery walls, leading to plaque formation. Plaque expansion is driven by monocyte infiltration where they differentiate into heterogeneous macrophage populations, including foamy macrophages. To understand genes that regulate monocyte differentiation toward foamy macrophages, we performed pseudotime analysis of murine scRNA-seq from atherosclerotic plaques. This analysis identified Trem2, a lipid sensor expressed on myeloid cells, as a potential regulator of foamy cell formation. These results were further supported by an in vitro genome-wide crispr screen performed on oxLDL-treated foamy macrophages, which identified Trem2 as a candidate regulator for oxLDL uptake. To test the role of macrophage Trem2 in atherosclerotic plaque formation, we generated Trem2 fl/fl CX3CR1 CreER LDLR -/- mice that delete Trem2 only in macrophages upon tamoxifen treatment (TAM). TAM enriched Western Diet (WD) feeding for 8 weeks lead to significantly decreased plaque formation in the aortic arch and aortic sinus of Trem-deficient mice compared to litermate control. Importantly, Trem2flox animals displayed comparable serum cholesterol levels to control mice following WD feeding. Finally, to determine whether Trem2 is required for foamy macrophage formation in vivo, we performed mixed bone marrow chimera of 50% Trem2 -/- marrow and 50% control marrow into Ldlr -/- recipients fed with western diet. Plaque associated Trem2-deficient macrophages failed to develop into foamy macrophages when in competition with WT macrophages, despite normal ratios of circulating monocytes. Overall, this data identifies Trem2 as a novel regulator of foamy macrophage formation and atherosclerotic plaque growth that could be targeted therapeutically to treat CVD.