Cytoprotective effects of C1s enzyme in macrophages in atherosclerosis mediated through the LRP5 and Wnt/β-catenin pathway

C1s enzyme (active C1s) is a subunit of the complement C1 complex that cleaves low-density lipoprotein receptor-related proteins 5 and 6, leading to Wnt/β-catenin pathway activation in some cell lines. Macrophages have two major functional polarization states (the classically activated M1 state and the alternatively activated M2 state) and play an essential role in atherosclerosis. An increasing amount of evidence suggests that canonical Wnt signaling is related to macrophage polarization. In this study, we explored the cytoprotective effects of C1s enzyme in macrophages. The results show that C1s enzyme activates canonical Wnt signaling in macrophages, exacerbates macrophage M2 polarization, and inhibits M1 polarization. Moreover, C1s enzyme reduces foam cell formation and simultaneously enhances efferocytosis. This study reveals a novel function of C1s enzyme in macrophages in the context of atherosclerosis.