Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe–/– mice during disease regression

Abstract

Experimental models of atherosclerosis suggest that recruitment of monocytes into plaques drives the progression of this chronic inflammatory condition. Cholesterol-lowering therapy leads to plaque stabilization or regression in human atherosclerosis, characterized by reduced macrophage content, but the mechanisms that underlie this reduction are incompletely understood. Mice lacking the gene Apoe (Apoe -/-mice) have high levels of cholesterol and spontaneously develop atherosclerotic lesions. Here, we treated Apoe -/-mice with apoEencoding adenoviral vectors that induce plaque regression, and investigated whether macrophage removal from plaques during this regression resulted from quantitative alterations in the ability of monocytes to either enter or exit plaques. Within 2 days after apoE complementation, plasma cholesterol was normalized to wild-type levels, and HDL levels were increased 4-fold. Oil red O staining and quantitative mass spectroscopy revealed that esterified cholesterol content was markedly reduced. Plaque macrophage content decreased gradually and was 72% lower than baseline 4 weeks after apoE complementation. Importantly, this reduction in macrophages did not involve migratory egress from plaques or CCR7, a mediator of leukocyte emigration. Instead, marked suppression of monocyte recruitment coupled with a stable rate of apoptosis accounted for loss of plaque macrophages. These data suggest that therapies to inhibit monocyte recruitment to plaques may constitute a more viable strategy to reduce plaque macrophage burden than attempts to promote migratory egress.

IL-17A Influences Essential Functions of the Monocyte/Macrophage Lineage and Is Involved in Advanced Murine and Human Atherosclerosis

“…In conclusion, the data clearly identify IL-17A as an independent and effective proinflammatory modulator in human plaque microenvironment that may promote plaque instability and plaque rupture; however, further studies are necessary to evaluate the relevance of the findings in the clinical setting. Because IL-17A is prominently involved in early and advanced atherosclerotic lesion formations, we further evaluated the underlying mechanisms by analyzing the impact of IL-17A on monocytes and monocyte-derived cells, which are known to play a major role during disease development and progression (4,33,34). Previous studies have convincingly shown that migratory egress of monocyte-derived cells is a major step (35), but reduction of monocyte recruitment seems to be even more important in reducing plaque monocyte-originated cells burden (4).…”

“…Because IL-17A is prominently involved in early and advanced atherosclerotic lesion formations, we further evaluated the underlying mechanisms by analyzing the impact of IL-17A on monocytes and monocyte-derived cells, which are known to play a major role during disease development and progression (4,33,34). Previous studies have convincingly shown that migratory egress of monocyte-derived cells is a major step (35), but reduction of monocyte recruitment seems to be even more important in reducing plaque monocyte-originated cells burden (4). We already showed that IL-17A inhibition reduces lesional chemokine expression (CCL5) in early atherosclerotic lesions and IL-17A induces expression of adhesion molecules on endothelial cells (VCAM-1) (5, 7).…”

“…Chronic inflammatory processes are important mechanisms that lead to atherosclerotic lesion development and progression (1). Recent studies have shown that plaque progression is predominantly caused by monocyte recruitment and/or local proliferation of macrophages (2,3), whereas plaque stabilization and regression is characterized by reduced macrophage accumulation due to predominantly reduced monocyte recruitment, but also migratory egress of macrophages (4).…”

HDL and Atherothrombotic Vascular Disease

“…This process causes the macrophages to transform into lipid-laden macrophage foam cells which can no longer escape the arterial wall (Potteaux et al 2011). The excessive cellular cholesterol in macrophage foam cells can be efficiently removed by the potent cholesterol acceptors lipid-free apoA-I and HDLs to be transported back to the liver by a process termed reverse cholesterol transport.…”

Mechanisms of Leukocyte Recruitment Into the Aorta During Atherosclerosis

“…New data also suggest that normalization of cholesterol can correct monocyte recruitment into the aorta and additionally, lead to decreased M content in atherosclerotic aortas. Treatment of Apoe -/-with apoE-encoding adenoviral vectors induced plaque regression, and attenuated CCR7-independent aortic M content (Potteaux et al, 2011). Thus, interfering with monocyte recruitment into and possible egress from atherosclerotic plaques may be therapeutically beneficial, in parallel with aggressive lipid lowering therapies, to maintain and reinforce the reduction in monocyte recruitment to the aorta.…”