Abstract Wed067: Plaque Macrophages Require Trem2 to Drive Necrotic Core Resolution and Atherosclerotic Plaque Regression

Cholesterol lowering therapies have allowed for the stabilization of atherosclerotic plaques in humans, leading to reduced rates of ischemic cardiac events. Further reduction of cholesterol levels has also been achieved with the recent broad application of PCSK9 inhibitors, which, in some patients, showed regression of total plaque volume by clinical imaging. However, the cellular mechanisms governing atherosclerosis regression and beneficial plaque remodeling remain poorly defined. We previously implicated Trem2, a lipid sensor expressed by cholesterol-loaded foam cells, as a key player in the modulation of atherosclerosis development through the preservation of foam cell survival and function. Further, single cell RNA sequencing analysis showed that plaque-associated myeloid cells upregulated Trem2 during plaque regression. Thus, we sought to test the function of Trem2 during regression. To model atherosclerosis regression in mice, we administered a liver-targeted AAV to drive expression of the murine Ldlr gene in hepatocytes of Ldlr -/- mice with established atherosclerotic plaques, promoting effective cholesterol control. We performed macrophage- or monocyte-specific Trem2 deletion during the regression using inducible deletion mouse models. Compared to baseline, we observed a 10-fold decrease in serum cholesterol levels in regressing mice and a significant reduction in plaque size. Using conditional deletion models, we found that Trem2 expression on plaque macrophages, but not newly recruited monocytes, was required for plaque regression while having no significant impact on circulating immune cells, body weight, or cholesterol levels. Deletion of Trem2 on plaque macrophages also impeded the resolution of necrotic cores in aortic sinus plaques during regression. Thus, Trem2-expressing plaque macrophages within lesions are key mediators of atherosclerotic plaque regression and facilitate beneficial plaque remodeling through enhanced efferocytosis. This suggests clinical efficacy of aggressive lipid-lowering therapies may depend on the efferocytic capacity of plaque foam cells, and that targeting the Trem2 pathway may represent a beneficial therapeutic strategy to stabilize plaques in patients receiving PCSK9 inhibitors.