Abstract
Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1Β (IL-1Β) is a key pro-inflammatory factor in innate antifungal immunity. 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-B-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. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 433-436 |
| Number of pages | 4 |
| Journal | Nature |
| Volume | 459 |
| Issue number | 7245 |
| DOIs | |
| Publication status | Published - May 21 2009 |
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Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. / Gross, Olaf; Poeck, Hendrik; Bscheider, Michael; Dostert, Catherine; Hannesschläger, Nicole; Endres, Stefan; Hartmann, Gunther; Tardivel, Aubry; Schweighoffer, Edina; Tybulewicz, Victor; Mócsai, A.; Tschopp, Jürg; Ruland, Jürgen.
In: Nature, Vol. 459, No. 7245, 21.05.2009, p. 433-436.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence
AU - Gross, Olaf
AU - Poeck, Hendrik
AU - Bscheider, Michael
AU - Dostert, Catherine
AU - Hannesschläger, Nicole
AU - Endres, Stefan
AU - Hartmann, Gunther
AU - Tardivel, Aubry
AU - Schweighoffer, Edina
AU - Tybulewicz, Victor
AU - Mócsai, A.
AU - Tschopp, Jürg
AU - Ruland, Jürgen
PY - 2009/5/21
Y1 - 2009/5/21
N2 - Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1Β (IL-1Β) is a key pro-inflammatory factor in innate antifungal immunity. 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-B-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. 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.
AB - Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1Β (IL-1Β) is a key pro-inflammatory factor in innate antifungal immunity. 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-B-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. 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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U2 - 10.1038/nature07965
DO - 10.1038/nature07965
M3 - Article
VL - 459
SP - 433
EP - 436
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7245
ER -