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Background: Monocytes play pivotal roles in atherosclerosis. Ly-6C low monocytes, also known as patrolling monocytes, become foamy in the circulation of mice with hyperlipidemia. However, the role of Ly-6C low monocytes in atherosclerosis with hypertriglyceridemia (HTG) remains to be determined. Aim: To examine the phenotypes and role of Ly-6C low monocytes in atherosclerosis in HTG. Method: Ldlr -/- ApoC3Tg (transgenic expression of human ApoC3) mice fed a western high-fat diet (WD) were used to examine the effects of HTG on monocyte lipid accumulation (foamy monocyte formation), phenotypes, and contributions to atherosclerosis. Results: Plasma triglycerides in Ldlr -/- ApoC3Tg mice were 5.1 times higher than in Ldlr -/- controls at 6 weeks on WD, correlating with more than twice the increase in aortic atherosclerosis (P<0.01). Consistently, Ly-6C low compared to Ly-6C high monocytes in Ldlr -/- mice had increased lipid accumulation and exhibited elevated levels of TNFα, IL-6, IL-1β, Plin2, and PPAR-γ. In Ldlr -/- ApoC3Tg mice, Ly-6C low (also CD11c + ) monocytes demonstrated even greater lipid accumulation and adhesion to VCAM-1 and had further elevations in levels of TNFα, IL-6, IL-1β, Plin2, and PPAR-γ than CD11c + (Ly-6C low ) monocytes in Ldlr -/- controls, indicating an enhanced inflammatory response and lipid accumulation under HTG. Furthermore, compared to Ldlr -/- control mice, Ldlr -/- ApoC3Tg mice had an increase in the level of SIRPα (a ligand of the “don’t-eat me” signal CD47) on Ly-6C low monocytes, indicative of impairment in efferocytosis and clearance of apoptotic cells. Additionally, nuclear c-Rel mRNA and protein levels were upregulated in Ly-6C low monocytes of Ldlr -/- ApoC3Tg mice compared to Ldlr -/- controls, suggesting activation of the NF-κB pathway in Ly-6C low monocytes by HTG. Finally, depletion of Ly-6C low monocytes reduced atherosclerosis by 45% (P<0.05) in Ldlr -/- ApoC3Tg mice, indicating a role of Ly-6C low monocytes in atherosclerosis in HTG. Conclusions: HTG accelerates atherogenesis in Ldlr -/- mice, possibly by increasing lipid accumulation and inflammatory phenotypic changes in monocytes, primarily CD11c + Ly-6C low monocytes.
Xiao et al. (Wed,) studied this question.