Complement-mediated ‘bystander’ damage initiates host NLRP3 inflammasome activation

• DOI: 10.1242/jcs.179291
• Publication Date: 2016-03-23T02:55:00Z
• Authors: Rahul Suresh; Prabha Chandrasek...; Fayyaz S. Sutterwala; David M. Mosser
• Keywords: Mice, Knockout; Mice, Inbred BALB C; Macrophages; Interleukin-1beta; Interleukin-18; Complement C5a; Bystander Effect; Complement Membrane Attack Complex; CARD Signaling Adaptor Proteins; Mice; HEK293 Cells; Phagocytosis; NLR Family, Pyrin Domain-Containing 3 Protein; Complement C3a; Animals; Humans; Th17 Cells; Apoptosis Regulatory Proteins

ABSTRACT 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 new mechanism that depends on the terminal complement components (C5b–C9). 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-1 activation 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 (also known as PYCARD) 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 T helper 17 cell (TH17) biasing. These findings reveal a new mechanism by which complement promotes inflammation and regulates innate and adaptive immunity.