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Macrophages release plasma membrane-derived particles rich in accessible cholesterol

Cuiwen He,Xuchen Hu,Thomas A. Weston,Rachel S. Jung,Jaspreet Sandhu,Song Huang,Patrick J. Heizer,Jason K. Kim,Rochelle M. Ellison,Jiake Xu,M. Kilburn,S. Bensinger,H. Riezman,P. Tontonoz,L. Fong,Haibo Jiang,S. Young

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Earlier studies suggested that particles are released from the macrophage plasma membrane, but the mechanism has been unclear. We found that filopodia of macrophages release large numbers of vesicular particles. Nanoscale secondary ion mass spectrometry revealed that these particles are enriched in cholesterol, including the “accessible” pool of cholesterol detectable by the cholesterol-binding protein. The cholesterol content of macrophage particles increased when the cells were loaded with cholesterol and could be depleted by incubating the cells with high-density lipoproteins. Our studies suggest that the release of particles by macrophages could be one mechanism for cholesterol efflux and that particles could be an intermediate in the movement of cholesterol to high-density lipoproteins. Macrophages are generally assumed to unload surplus cholesterol through direct interactions between ABC transporters on the plasma membrane and HDLs, but they have also been reported to release cholesterol-containing particles. How macrophage-derived particles are formed and released has not been clear. To understand the genesis of macrophage-derived particles, we imaged mouse macrophages by EM and nanoscale secondary ion mass spectrometry (nanoSIMS). By scanning EM, we found that large numbers of 20- to 120-nm particles are released from the fingerlike projections (filopodia) of macrophages. These particles attach to the substrate, forming a “lawn” of particles surrounding macrophages. By nanoSIMS imaging we showed that these particles are enriched in the mobile and metabolically active accessible pool of cholesterol (detectable by ALO-D4, a modified version of a cholesterol-binding cytolysin). The cholesterol content of macrophage-derived particles was increased by loading the cells with cholesterol or by adding LXR and RXR agonists to the cell-culture medium. Incubating macrophages with HDL reduced the cholesterol content of macrophage-derived particles. We propose that release of accessible cholesterol-rich particles from the macrophage plasma membrane could assist in disposing of surplus cholesterol and increase the efficiency of cholesterol movement to HDL.

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