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Innate immune proteins C1q and mannan-binding lectin enhance clearance of atherogenic lipoproteins by human monocytes and macrophages.

ABSTRACT: Atherosclerosis is a chronic inflammatory disorder that is characterized by the accumulation of modified lipoproteins in the arterial intima. C1q and mannan-binding lectin (MBL) are not only recognition components involved in activation of inflammation via the complement cascade, but they are also able to directly modulate phagocyte activation. Studies in C1q(-/-) and MBL(-/-) mice suggest that these molecules play a protective role in the early atherosclerotic lesion in the absence of, or prior to, expression of other complement components. However, in later stages, complement activation becomes an inappropriate inflammatory response, contributing to disease pathology. Therefore, to investigate possible molecular interactions of C1q and MBL in atherosclerotic lesions, we examined the influence of C1q and MBL in the clearance of native and modified lipoproteins by human monocytes and monocyte-derived macrophages. Both C1q and MBL are shown to bind and enhance the monocyte/monocyte-derived macrophage clearance of modified forms of low-density lipoprotein (LDL), including oxidized LDL and acetylated LDL, but not native LDL. Modified forms of LDL activate the classical complement pathway, but no lectin pathway activation was detected. Interestingly, monocytes that ingested modified LDL in the presence of C1q or MBL upregulated surface CD80 and CD31, as well as CCL2 chemokine gene expression. However, C1q and MBL also significantly reduced levels of free cholesterol accumulation in monocytes and human monocyte-derived macrophages that ingested oxidized LDL, while enhancing high-density lipoprotein-specific cholesterol efflux from these cells. These results suggest a novel pathway in which C1q and MBL influence removal and metabolism of atherogenic forms of LDL in the early stages of atherosclerosis.


PROVIDER: S-EPMC3334294 | BioStudies | 2010-01-01

REPOSITORIES: biostudies

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