title: Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome.
abstract: Production of the proinflammatory cytokine interleukin 1β (IL-1β) by dendritic cells is crucial in host defense. Here we identify a previously unknown role for dectin-1 in the activation of a noncanonical caspase-8 inflammasome in response to fungi and mycobacteria. Dectin-1 induced both the production and maturation of IL-1β through signaling routes mediated by the kinase Syk. Whereas the CARD9-Bcl-10-MALT1 scaffold directed IL1B transcription, the recruitment of MALT1-caspase-8 and ASC into this scaffold was crucial for processing of pro-IL-1β by caspase-8. In contrast to activation of the canonical caspase-1 inflammasome, which requires additional activation of cytosolic receptors, activation of the noncanonical caspase-8 inflammasome was independent of pathogen internalization. Thus, dectin-1 acted as an extracellular sensor for pathogens that induced both IL-1β production and maturation through a noncanonical caspase-8-dependent inflammasome for protective immunity.
authors.affiliation: Center of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. s.i.gringhuis@amc.uva.nl
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Gringhuis
authors.forename: Tanja M
authors.initials: TM
authors.lastname: Kaptein
authors.forename: Brigitte A
authors.initials: BA
authors.lastname: Wevers
authors.forename: Bart
authors.initials: B
authors.lastname: Theelen
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Vlist
authors.forename: Teun
authors.initials: T
authors.lastname: Boekhout
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
mesh_terms: D002176:Candida albicans / Q000276:immunology; D053181:Caspase 8 / Q000276:immunology*; D004789:Enzyme Activation; D005110:Extracellular Space / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D009161:Mycobacterium / Q000276:immunology; D015398:Signal Transduction; D000099181:Dectin-1
chemical_list: D053181:Caspase 8; D058847:Inflammasomes; D053583:Interleukin-1beta; D037181:Lectins, C-Type; C546929:CLEC7A protein, human; D000099181:Dectin-1; C505530:CASP8 protein, human