title: Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.
abstract: Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1beta (IL-1beta) is a key pro-inflammatory factor in innate antifungal immunity. The mechanism by which the mammalian immune system regulates IL-1beta production after fungal recognition is unclear. Two signals are generally required for IL-1beta production: an NF-kappaB-dependent signal that induces the synthesis of pro-IL-1beta (p35), and a second signal that triggers proteolytic pro-IL-1beta processing to produce bioactive IL-1beta (p17) via Caspase-1-containing multiprotein complexes called inflammasomes. 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-1beta synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signalling for pro-IL-1beta 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-1beta 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-1beta production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.
authors.affiliation: III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Gross
authors.forename: Hendrik
authors.initials: H
authors.lastname: Poeck
authors.forename: Michael
authors.initials: M
authors.lastname: Bscheider
authors.forename: Catherine
authors.initials: C
authors.lastname: Dostert
authors.forename: Nicole
authors.initials: N
authors.lastname: Hannesschläger
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.forename: Aubry
authors.initials: A
authors.lastname: Tardivel
authors.forename: Edina
authors.initials: E
authors.lastname: Schweighoffer
authors.forename: Victor
authors.initials: V
authors.lastname: Tybulewicz
authors.forename: Attila
authors.initials: A
authors.lastname: Mocsai
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland