Complement-mediated “bystander” damage initiates host NLRP3 inflammasome activation

Complement activation has long been associated with inflammation, primarily due to the elaboration of the complement anaphylotoxins, C5a and C3a. In this work, we demonstrate that the phagocytosis of complement-opsonized particles promotes host inflammatory responses by a novel mechanism that depends on the terminal complement components (C5b-9).We demonstrate that during the phagocytosis of complement-opsonized particles, the membrane attack complex (MAC) of complement can be transferred from the activating particle to the macrophage plasma membrane, by a “bystander” mechanism. This MAC-mediated bystander damage initiates NLRP3 inflammasome activation, resulting in caspase-1activation and IL-1β and IL-18 secretion. Inflammasome activation is not induced when macrophages phagocytize unopsonized particles or particles opsonized with serum deficient in one of the terminal complement components. The secretion of IL-1β and IL-18 by macrophages depends on NLRP3, ASC, and caspase-1, as macrophages deficient in any one of these components fail to secrete these cytokines following phagocytosis. The phagocytosis of complement-opsonized particles increases leukocyte recruitment and promotes TH17 biasing. These findings reveal a novel mechanism by which complement promotes inflammation and regulates innate and adaptive immunity.