Trichothecene mycotoxins activate NLRP3 inflammasome through a P2X7 receptor and Src tyrosine kinase dependent pathway |
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Authors: | Pä ivi Kankkunen,Elina Vä limä ki,Johanna Rintahaka,Jaana Palomä ki,Tuula Nyman,Harri Alenius,Henrik Wolff,Sampsa Matikainen |
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Affiliation: | 1. Finnish Institute of Occupational Health (FIOH), Topeliuksenkatu 41A, 00250 Helsinki, Finland;2. Institute of Biotechnology, University of Helsinki, Finland |
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Abstract: | Inflammasome is an intracellular molecular platform of the innate immunity that is a key mediator of inflammation. The inflammasome complex detects pathogens and different danger signals, and triggers cysteine protease caspase-1-dependent processing of pro-inflammatory cytokines IL-1β, and IL-18 in dendritic cells and macrophages. Previously, we have shown that water-damaged building associated trichothecene mycotoxins, including roridin A, trigger IL-1β and IL-18 secretion in human macrophages. However, the molecular basis as well as mechanism behind this trichothecene-induced cytokine secretion has remained uncharacterized. Here, we show that the trichothecene-induced IL-1β secretion is dependent on NLRP3 inflammasome in human primary macrophages. Pharmacological inhibition and small interfering RNA approach showed that the trichothecene-induced NLRP3 inflammasome activation is mediated through ATP-gated P2X7 receptor. Moreover, we show that trichothecene-triggered NLRP3 inflammasome activation is dependent on Src tyrosine kinase activity. In addition, gene silencing of c-Cbl, a negative autophagy-related regulator of c-Src, resulted in enhanced secretion of IL-1β and IL-18 in response to trichothecene mycotoxin stimulation in human macrophages. In conclusion, our results suggest that roridin A, a fungal trichothecene mycotoxin, acts as microbial danger signals that trigger activation of NLRP3 inflammasome through P2X7R and Src tyrosine kinase signaling dependent pathway in human primary macrophages. |
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Keywords: | AG126, tyrphostin AG 126 AZ, AZ11645373 DAMP, danger associated molecular pattern NLR, NOD-like nucleotide-binding oligomerization domain NLRP, NLR family, Pyrin domain containing PP2, 4-amino-3-(4-chlorophenyl)-1-(t-butyl)-1H-pyrazolo[3,4-d]pyrimidine, RLR, RIG-I-like receptors RU, relative unit siRNA, small ribonucleic acid interference |
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