title: Complement-mediated 'bystander' damage initiates host NLRP3 inflammasome activation.
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.
authors.affiliation: Department of Cell Biology and Molecular Genetics and the Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Suresh
authors.affiliation: Department of Cell Biology and Molecular Genetics and the Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA.
authors.forename: Prabha
authors.initials: P
authors.lastname: Chandrasekaran
authors.affiliation: The Inflammation Program, Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: Department of Cell Biology and Molecular Genetics and the Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA dmosser@umd.edu.
authors.forename: David M
authors.identifier: 0000-0002-9503-4187
authors.initials: DM
authors.lastname: Mosser
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D024201:Bystander Effect / Q000235:genetics / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins; D015926:Complement C3a / Q000235:genetics / Q000276:immunology*; D015936:Complement C5a / Q000235:genetics / Q000276:immunology*; D015938:Complement Membrane Attack Complex / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000276:immunology*; D010587:Phagocytosis / Q000235:genetics; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D015938:Complement Membrane Attack Complex; C587672:IL1B protein, mouse; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D015926:Complement C3a; D015936:Complement C5a
keywords: ASC; Bystander activation; Caspase; Complement; IL-18; IL-1β; Inflammasome; Membrane attack complex; NLRP3; Phagocytosis; TH17