Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence

Beating anti-fungal defences Immunocompromised individuals are at high risk from fungal infection, yet the molecular mechanisms that govern host defence against fungi are not well understood. Gross et al . now show that Candida albicans infection in mice activates the NALP3 inflammasome via a mechanism involving Sky-induced production of reactive oxygen induced by the tyrosine kinase Syk. Interleukin-1β (IL-1β) is a key pro-inflammatory factor in innate antifungal immunity, but the mechanism by which the mammalian immune system regulates IL-1β production after fungal recognition is unclear. Here it is demonstrated that the tyrosine kinase Syk controls both pro-IL-1β synthesis and Nlrp3 inflammasome activation after cell stimulation with Candida albicans . Fungal infections represent a serious threat, particularly in immunocompromised patients 1 . Interleukin-1β (IL-1β) is a key pro-inflammatory factor in innate antifungal immunity 2 . 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 inflammasomes 3 . 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 mol