Complement protein C1q suppresses macrophage inflammasome activation during clearance of modified LDL

Abstract

Abstract In the atherosclerotic environment, inflammation plays a major role. Ingestion of modified forms of low-density lipoproteins (such as oxidized LDL) by macrophages promotes macrophage secretion of inflammatory cytokines, which contributes to disease progression. We have previously shown that the complement classical pathway activator, C1q, has a novel, anti-inflammatory role independent of the complement cascade: opsonization of modified LDL with C1q polarizes macrophages towards an anti-inflammatory (M2) phenotype, and dampens the pro-inflammatory (M1) phenotype that is prevalent in the atherosclerotic environment. Differential transcriptomic analysis in human macrophages suggests that C1q may influence macrophage inflammatory phenotype by modulating the levels of components of the NLRP3 inflammasome, a protein complex responsible for activation of inflammatory cytokine IL-1β. To investigate this further, resting or M1-polarized human monocyte derived macrophages (HMDMs) were treated with 10 μg protein/mL oxLDL, with or without 75 μg/mL C1q, and inflammasome gene, protein and activity were measured. Our data suggest that when bound to oxLDL, C1q downregulates NLRP3 inflammasome related genes, and reduces inflammasome activity, leading to a reduction in IL-1β secretion from M1-polarized macrophages. This indicates that this non-complement role of C1q may be important in dampening inflammation in the early atherosclerotic lesion. Discerning the molecular pathways that regulate inflammatory states of macrophages can contribute to the development of therapeutics for chronic inflammatory illnesses such as atherosclerosis.