Pivotal Advance: Macrophages become resistant to cholesterol-induced death after phagocytosis of apoptotic cells

被引:57
作者
Cui, Dongying
Thorp, Edward
Li, Yankun
Wang, Nan
Yvan-Charvet, Laurent
Tall, Alan R.
Tabas, Ira
机构
[1] Columbia Univ, Dept Med, New York, NY 10032 USA
[2] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA
[3] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA
关键词
apoptosis; atherosclerosis; cell survival; efferocytosis;
D O I
10.1189/jlb.0307192
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
One of the most important functions of macrophages is the phagocytosis of apoptotic cells (ACs). ACs deliver large amounts membrane-derived cholesterol to phagocytes, which, if not handled properly, can be cytotoxic. In atherosclerosis, where the ACs are cholesterol-loaded, this situation is exaggerated, because the ACs deliver both endogenous membrane cholesterol and stored lipoprotein-derived cholesterol. To examine how phagocytes handle this very large amount of cholesterol, we incubated macrophage phagocytes with cholesterol-loaded ACs. Our results show that the phagocytes call into play a number of cellular responses to protect them from cholesterol-induced cytotoxicity. First, through efficient trafficking of the internalized AC-derived cholesterol to acyl-CoA:cholesterol acyltransferase (ACAT) in the endoplasmic reticulum, phagocytes efficiently esterify the cholesterol and thus prevent its toxic effects. However, the phagocytes show no signs of cytotoxicity even when ACAT is rendered dysfunctional, as might occur in advanced atherosclerotic lesions. Under these conditions, the phagocytes remain viable through massive efflux of AC-derived cholesterol. Remarkably, these phagocytes still show a survival response even when high cholesterol levels are maintained in the post-phagocytosis period by subsequent incubation with atherogenic lipoproteins, as also may occur in atheromata. In this case, death in phagocytes is prevented by activation of survival pathways involving PI-3 kinase/Akt and NF-kappa B. Thus, macrophages that have ingested AG successfully employ three survival mechanisms-cholesterol esterification, massive cholesterol efflux, and cell-survival signaling. These findings have implications for macrophage physiology in both AC clearance and atherosclerotic plaque progression.
引用
收藏
页码:1040 / 1050
页数:11
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