Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome

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.