Abstract 160: Atherosclerosis Regression At The Single-Cell Level

Abstract

Atherosclerosis is a chronic inflammatory disease, but lipid-lowering therapies continue to be the standard of care, and substantial regression of human atheromata remains an elusive goal. To address this gap, our lab has devised multiple models to achieve plaque regression in atherosclerotic mice using genetic or RNA-based approaches. Here, we set out to learn how the immune cell composition of murine plaques changes with the induction of a regression phenotype irrespective of model. To achieve this, we performed single cell RNA-seq on CD45 + leukocytes from the aortic arch plaques of Ldlr -/- mice fed an atherogenic diet (baseline progression) and from two additional cohorts that were switched to control chow following atherogenesis and either treated with antisense oligonucleotides targeting ApoB (regression) or not (halted progression). The resultant transcriptomic data were integrated with those from our previous regression studies in a batch-corrected manner to distill the common features of atherosclerosis regression. This approach yielded a dataset of 35,996 cells, a degree of granularity one order of magnitude higher than that of the average comparable study, which allowed us to draw a comprehensive picture of the lymphoid and myeloid transcriptional dynamics that give rise to pro-resolving phenotypes. Specifically, we found two novel macrophage populations with distinct transcriptional profiles and unique distribution across conditions that nonetheless shared the same differentiation path. The first was characteristic of the halted progression groups and showed upregulation of genes involved in oxidative phosphorylation; the other was enriched in regression and displayed a transcriptional program consistent with plaque remodeling by means of efferocytosis and cholesterol efflux. Our findings suggest that pro-resolving macrophage fate acquisition in regression occurs at the expense of a separate, potentially pro-inflammatory lineage. A deeper understanding of the molecular and cellular purview of these pro-resolving macrophages as well as the ontogenic path of bone marrow monocytes toward that fate would contribute to the development of anti-inflammatory therapies to treat and prevent atherosclerosis.