Abstract Body: Macrophages are key cells in atherosclerotic cardiovascular disease. Macrophages within a single plaque are heterogenous: some are lipid-laden “foam cells” with varying ability to recycle lipoproteins or clear dead cells while others secrete traditional “pro-inflammatory” signals. Determining what signals bias macrophages to one phenotype versus another could identify a therapeutic target. Our lab showed that after acute myocardial infarction, macrophages are skewed to a reparative phenotype by loss of cGAS-STING signaling. cGAS-STING are a pattern recognition receptor-adaptor pair that are activated by double stranded DNA in a sequence-independent manner. Global deletion of Sting and Cgas have been shown to protect against atherosclerosis in mice. We hypothesize that hematopoietic-specific loss of Cgas will reduce plaque burden by biasing macrophages to a less inflammatory phenotype and upregulating pro-resolving functions. To test this, B6.129S7-Ldlr^tm1Her/J (Ldlr-/-) mice (female, age 8-12 weeks, 9 per group) underwent total body irradiation followed by bone marrow transplant from C57BL6/N-Cgas-/- (Cgas-/-) or wildtype donor mice (female, age 6-8 weeks). After bone marrow reconstitution, recipient mice were started on Western diet. Mice will continue Western diet for 12 weeks (through April 24, 2024). Then, aortas, peripheral blood, spleen, and bone marrow will be collected for further analysis including plaque burden, fibrous cap thickness, and macrophage phenotype. We will also perform in vitro studies using primary macrophages to determine how Cgas-/- affects macrophage effector functions critical for atherosclerosis. To date, mice that received Cgas-/- or wildtype donor bone marrow had similar baseline cell count, triglyceride and total cholesterol levels. Bone marrow derived macrophages (BMDM) from Cgas-/- mice have increased expression of fibronectin. Thus, at baseline Cgas-/- BMDM express high levels of a marker associated with pro-reparative macrophages. More studies are needed to characterize this phenotype and determine the consequence for in vivo atherosclerosis.