Complement component C1q regulates macrophage expression of Mer tyrosine kinase to promote clearance of apoptotic cells (171.31)

Abstract

Abstract Failure to efficiently clear apoptotic cells is linked to defects in development and autoimmunity. Complement component C1q is required for efficient clearance of apoptotic cells, and C1q deficiency is the strongest known susceptibility factor for autoimmunity associated with lupus. Despite the importance of C1q in apoptotic cell clearance, the mechanism by which C1q enhances apoptotic cell clearance is poorly understood. Here we describe a novel C1q-dependent engulfment mechanism for apoptotic cells. We found that macrophage activation with C1q resulted in cycloheximide-sensitive enhanced engulfment, indicating a requirement for de novo protein synthesis. To investigate the cycloheximide-sensitive pathway, C1q-elicited macrophage transcripts were identified by microarray. C1q triggered the expression of Mer tyrosine kinase and Gas 6: a receptor-ligand pair that mediates clearance of apoptotic cells. This novel pathway is specific to C1q since MBL, a related collectin, failed to upregulate Mer expression and function. Soluble Mer-Fc fusion protein inhibited C1q-dependent engulfment of apoptotic cells. In addition, Mer-/- macrophages failed to respond to C1q with enhanced engulfment of apoptotic cells, indicating a requirement for Mer. Our results suggest that C1q elicits a macrophage phenotype specifically tailored for apoptotic cell clearance, and these data are consistent with the established requirement for C1q in prevention of autoimmunity.