title: C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation.
abstract: Interleukin-1β (IL-1β) is a proinflammatory cytokine and a therapeutic target in several chronic autoimmune states. Monocytes and macrophages are the major sources of IL-1β. IL-1β production by these cells requires Toll-like receptor (TLR) and adenosine triphosphate (ATP)-mediated P2X purinoceptor 7 (P2X7) signals, which together activate the inflammasome. However, how TLR signals and ATP availability are regulated during monocyte activation is unclear and the involvement of another danger signal system has been proposed. Here, we demonstrate that both lipopolysaccharide (LPS) and the anaphylatoxin C3a are needed for IL-1β production in human macrophages and dendritic cells, while in monocytes, C3a enhanced the secretion of LPS-induced IL-1β. C3a and LPS-stimulated monocytes increased T helper 17 (Th17) cell induction in vitro, and human rejecting, but not nonrejecting, kidney transplant biopsies were characterized by local generation of C3a and monocyte and Th17 cell infiltration. Mechanistically, C3a drives IL-1β production in monocytes by controlling the release of intracellular ATP into the extracellular space via regulation of as-yet unidentified ATP-releasing channels in an extracellular signal-regulated kinase 1/2-dependent fashion. These data define a novel function for complement in inflammasome activation in monocytes and suggest that C3aR-mediated signaling is a vital component of the IL-1β-Th17 axis.
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, London, United Kingdom;
authors.forename: Elham
authors.initials: E
authors.lastname: Asgari
authors.forename: Gaelle
authors.initials: G
authors.lastname: Le Friec
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Esperanza
authors.initials: E
authors.lastname: Perucha
authors.forename: Steven S
authors.initials: SS
authors.lastname: Sacks
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Claudia
authors.initials: C
authors.lastname: Kemper
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D003176:Complement C3 / Q000819:agonists / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism; D004789:Enzyme Activation; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D053583:Interleukin-1beta / Q000378:metabolism*; D016030:Kidney Transplantation; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D016177:Macrophage-1 Antigen / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D058486:Receptors, Purinergic P2X7 / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D058504:Th17 Cells / Q000378:metabolism; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: C038245:C3 protein, human; D002352:Carrier Proteins; D003176:Complement C3; D016207:Cytokines; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; D000255:Adenosine Triphosphate