Interaction of CR1 with Par3/Par6 polarity complex mediates anti-inflammatory reprogramming of neutrophils during phagocytosis. (61.1)

Abstract Partitioning defective protein 6 (Par6) belongs to a family of proteins first discovered to mediate partitioning in C. elegans. In mammals, the Par family of proteins is involved in several critical functions such as cell polarity, vesicle trafficking, cell migration, and signal transduction. Presence of Par proteins in T cells, suggests that spatial polarity could play important roles in mediating and/or regulating immune responses. Our data demonstrate that Par proteins, particularly as Par3/Par6/aPKC polarity complex, regulate neutrophil responses during phagocytosis. Our results show that during complement-mediated phagocytosis, engagement complement receptor 1 (CR1) by complement-opsonized particles, promotes the interaction between Par6/Par3 complex and CR1. The binding between CR1 and the Par complex is mediated by the interaction of the PDZ motifs found in the cytoplasmic domain CR1 with the PDZ domains of Par6/Par3. During IgG- and complement-mediated phagocytosis, ligation of CR1 by complement fragments, inhibits FcgammaR-induced ROS production as well as the FcgammaR-mediated release of pro-inflammatory cytokines . In conclusion, our data suggest that during phagocytosis, engagement of CR1 by complement fragments, down regulates the IgG-mediated pro-inflammatory response by disrupting the temporal/spatial assembly of the inflammatory complex at the sites of phagocytosis.