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PURPOSE OF REVIEW: Macrophages can accumulate lipid droplets in their cytoplasm resulting in the foamy appearance seen in various diseases, especially atherosclerosis. This review assesses new insights from single cell analyses into the role of different human macrophage subpopulations and genetic risk in atherosclerotic disease.RECENT FINDINGS: Single cell transcriptomic studies have identified TREM2hi foamy macrophages as a key population in both human and mouse atherosclerotic plaques. In addition, a TREM1hi/PLIN2hi population in human plaques has pro-inflammatory properties. Combined single cell transcriptomic and epigenetic multiomic profiling identified a population of CD52hi lipid-handling macrophages that are enriched for heritability of atherosclerotic disease. Molecular mechanisms have been identified linking gene-regulatory effects of disease-associated polymorphisms to the macrophage response to ox-LDL.SUMMARY: Recent studies have used singe cell approaches to provide new insights into macrophage subsets, their interactions with lipid species and their role in mediating genetic influences on disease risk.