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Published online before print June 18, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0307192

Received for publication March 28, 2007.
Revised May 22, 2007.
Accepted for publication May 27, 2007.

Article

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

Dongying Cui ^*, Edward Thorp ^*, Yankun Li ^*, Nan Wang ^*, Laurent Yvan-Charvet ^*, Alan R. Tall ^*, and Ira Tabas ^*@

Departments of *Medicine, Physiology and Cellular Biophysics, and Pathology and Cell Biology, Columbia University, New York, New York, USA

^@ To whom correspondence should be addressed. E-mail: iat1{at}columbia.edu.

	Abstract

One of the most important functions of macrophages is the phagocytosis 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-B. Thus, macrophages that have ingested ACs successfully employ three survival mechanisms--cholesterol esterification, massive cholesterol efflux, and cell-survival signaling. These data have implications for macrophage physiology in both AC clearance and atherosclerotic plaque progression.

Key Words: apoptosis • atherosclerosis • cell survival • efferocytosis

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