Complement mediated phagocytosis induces the activation of the NALP3 Inflammasome (INC5P.331)

Abstract

Abstract The Complement System is an important component of innate immunity, whose activation has been associated with acute inflammation. Activation of complement leads to the generation of a Membrane Attack Complex (MAC) composed of C5b-C9. The function of the MAC has been primarily associated with target cell death though the polymerization and insertion of C9 on the surface of the activating particle. In this study we provide evidence that MAC assembled on the surface of complement activating particles, can be transferred to host macrophages during the process of phagocytosis. This “bystander activation” onto macrophages causes potassium efflux and ROS production, which can induce the activation of the NALP3 inflammasome. The activation of caspase-1 then induces the secretion of IL-1β and IL-18 to regulate both innate and adaptive immunity. We show that macrophages activated by MAC, can induce T cell differentiation into Th17 cells when used as APCs. This study demonstrates that the phagocytosis of complement-opsonized particles can induce inflammasome activation by a novel mechanism involving MAC mediated “bystander” activation of host macrophages. This work provides another mechanism whereby complement activation can lead to acute inflammation and it emphasizes the importance of a previously undescribed function of the MAC to activate inflammasomes on phagocytic macrophages.