Aortic intima microenvironment instructs macrophage gene expression signature in steady state and progressing atherosclerosis

Abstract

Abstract Macrophages reside in the vascular intima of the aorta in plaque prone regions. Intima macrophages were found to be ‘tissue resident’, possessing the ability to self-renew independent of circulating monocytes and having a unique dependence on Csf1 and Flt3 pathways for development. Lineage tracing and depletion experiments showed these cells were regulators of early plaque development in models of atherosclerosis. Using bulk RNAseq on intima resident macrophages and single cell sequencing data from total leukocytes from C57Bl/6 mouse aorta, we identified a core gene expression profile associated with intima resident macrophages. Comparing this gene signatures to single-cell gene expression data obtained from total leukocytes from atherosclerotic aortas identified overlapping gene expression with foamy macrophages, despite foamy macrophages developing exclusively from recruited monocytes at this stage of disease. The intima resident gene signature was expressed in foamy cells in addition to cholesterol handling genes, but not in newly recruited monocytes. Importantly, the intima gene signature was only associated with cells lacking expression of inflammatory genes. Together this suggests there is a niche-driven gene expression program within the aortic intima influencing macrophage differentiation and function. Targeting this newly identified gene set may be important for regulation of the inflammatory pathways and foamy macrophage differentiation in atherosclerosis.