Complement protein C1q modulates lipoprotein metabolism in macrophage foam cells

Abstract

Abstract In the atherosclerotic lesion, macrophages ingest high levels of damaged, modified, low density lipoproteins (LDL), which accumulate in lipid droplets or defective lysosomes, generating macrophage foam cells which contribute to plaque instability and rupture. C1q, the recognition component of the classical complement cascade, opsonizes modified forms of LDL such as oxidized LDL, and promotes ingestion by macrophages. C1q has been shown to be protective in an atherosclerosis model in vivo and shown to improve macrophage foam cell survival in vitro. Autophagy is a catabolic pathway that plays a role in cellular survival and is an important process in many phagocytic cells, such as macrophages. We tested the hypothesis that C1q modulates macrophage lysosomal maturation during ingestion of oxLDL and increases autophagy in an atheroprotective manner to improve macrophage survival. Levels of autophagy initiation and elongation proteins, Beclin 1 and Atg5, are not modulated by C1q, but levels of autophagosome-associated proteins, LC3B-II and p62, were increased in immunoblot. Quantitative PCR revealed that the increase in p62 protein levels was not due to an increase in transcription. Immunofluorescence microscopy verified that the increase in LC3B and p62 by C1q resulted in an increase in autophagosome formation during oxLDL clearance. TEM verified the formation of double membrane vesicles. C1q also increased lysosomal acidification in macrophages during ingestion of oxLDL. These atheroprotective alterations to lipoprotein metabolism may be important in slowing disease progression, and provide insight into the protective role of C1q in early atherosclerosis.