Cell-specific and athero-protective roles for RIPK3 in a murine model of atherosclerosis

Abstract

Receptor-interacting protein kinase 3 (RIPK3) was recently implicated in promoting atherosclerosis progression through a proposed role in macrophage necroptosis. However, RIPK3 has been connected to numerous other cellular pathways, which raises questions about its actual role in atherosclerosis. Furthermore, RIPK3 is expressed in a multitude of cell types, suggesting that it may be physiologically relevant to more than just macrophages in atherosclerosis. In this study, <i>Ripk3</i> was deleted in macrophages, endothelial cells, vascular smooth muscle cells or globally on the <i>Apoe^-/-</i> background using Cre-lox technology. To induce atherosclerosis progression, male and female mice were fed a Western diet for three months before tissue collection and analysis. Surprisingly, necroptosis markers were nearly undetectable in atherosclerotic aortas. Furthermore, <i>en face</i> lesion area was increased in macrophage- and endothelial-specific deletions of <i>Ripk3</i> in the descending and abdominal regions of the aorta<i>.</i> Analysis of bone-marrow-derived macrophages and cultured endothelial cells revealed that <i>Ripk3</i> deletion promotes expression of monocyte chemoattractant protein 1 (MCP-1) and E-selectin in these cell types, respectively. Western blot analysis showed upregulation of MCP-1 in aortas with <i>Ripk3</i>-deficient macrophages. Altogether, these data suggest that RIPK3 in macrophages and endothelial cells protects against atherosclerosis through a mechanism that likely does not involve necroptosis. This protection may be due to RIPK3-mediated suppression of pro-inflammatory MCP-1 expression in macrophages and E-selectin expression in endothelial cells. These findings suggest a novel and unexpected cell-type specific and athero-protective function for RIPK3.This article has an associated First Person interview with the first author of the paper.