Fungal infections represent a serious threat, particularly in immunocompromised patients1. Interleukin-1β (IL-1β) is a key pro-inflammatory factor in innate antifungal immunity2. The mechanism by which the mammalian immune system regulates IL-1β production after fungal recognition is unclear. Two signals are generally required for IL-1β production: an NF-κB-dependent signal that induces the synthesis of pro-IL-1β (p35), and a second signal that triggers proteolytic pro-IL-1β processing to produce bioactive IL-1β (p17) via Caspase-1-containing multiprotein complexes called inflammasomes3. Here we demonstrate that the tyrosine kinase Syk, operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL-1β synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signalling for pro-IL-1β synthesis selectively uses the Card9 pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmalogical inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (also known as NALP3) was identified as the critical NOD-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (Pycard) for Caspase-1 (Casp1) activation and pro-IL-1β processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, we show that Nlrp3-deficient mice are hypersusceptible to Candida albicans infection. Thus, our results demonstrate the molecular basis for IL-1β production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.
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We thank C. Peschel for helpful conversations, K. Schroder for critically reading the manuscript, RIGEL Inc. for providing the Syk inhibitor R406, P. Vandenabeele for the anti-Caspase-1 antibody and V. Dixit for Nlrc4-/- mice. O.G. is supported by a Marie Curie RTN ApopTrain Fellowship. This work was supported by Swiss National Science Foundation National Center of Competence in Research molecular oncology and Mugen grants to J.T., an EMBO long-term fellowship to C.D. and a Max-Eder-Program grant from Deutsche Krebshilfe and Sonderforschungsbereich grants from Deutsche Forschungsgemeinschaft to J.R.
Author Contributions O.G., H.P. and J.R. designed the research; O.G., H.P., M.B., N.H., C.D. and A.T. performed experiments; E.S., V.T. and A.M. contributed critical reagents, O.G., H.P., M.B., S.E., G.H., C.D., J.T. and J.R. analysed results; O.G. made the figures; O.G., H.P. and J.R. wrote the paper.
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Gross, O., Poeck, H., Bscheider, M. et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433–436 (2009). https://doi.org/10.1038/nature07965
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