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CARD9 negatively regulates NLRP3-induced IL-1? production on Salmonella infection of macrophages.

ABSTRACT: Interleukin-1? (IL-1?) is a proinflammatory cytokine required for host control of bacterial infections, and its production must be tightly regulated to prevent excessive inflammation. Here we show that caspase recruitment domain-containing protein 9 (CARD9), a protein associated with induction of proinflammatory cytokines by fungi, has a negative role on IL-1? production during bacterial infection. Specifically, in response to activation of the nucleotide oligomerization domain receptor pyrin-domain containing protein 3 (NLRP3) by Salmonella infection, CARD9 negatively regulates IL-1? by fine-tuning pro-IL-1? expression, spleen tyrosine kinase (SYK)-mediated NLRP3 activation and repressing inflammasome-associated caspase-8 activity. CARD9 is suppressed during Salmonella enterica serovar Typhimurium infection, facilitating increased IL-1? production. CARD9 is, therefore, a central signalling hub that coordinates a pathogen-specific host inflammatory response.

SUBMITTER: Pereira M

PROVIDER: S-EPMC5052644 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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CARD9 negatively regulates NLRP3-induced IL-1β production on Salmonella infection of macrophages.

Pereira Milton M Tourlomousis Panagiotis P Wright John J P Monie Tom T Bryant Clare E CE

Nature communications 20160927

Interleukin-1β (IL-1β) is a proinflammatory cytokine required for host control of bacterial infections, and its production must be tightly regulated to prevent excessive inflammation. Here we show that caspase recruitment domain-containing protein 9 (CARD9), a protein associated with induction of proinflammatory cytokines by fungi, has a negative role on IL-1β production during bacterial infection. Specifically, in response to activation of the nucleotide oligomerization domain receptor pyrin-do ...[more]

PMID: 27670879

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Project description:Pseudomonas aeruginosa remains a leading cause of nosocomial and serious life-threatening infections, and contributes to increased mortality in immunocompromised individuals. P. aeruginosa infection triggers host immune response and often provokes potent inflammatory mediators, which do not necessarily eradicate the causative pathogen. On the other hand, it causes severe airway damage and eventually decreased lung function. Such unfavorable outcomes of inflammatory injury have necessitated the development of novel effective agents that can combat with P. aeruginosa-mediated inflammation. Herein, we investigated the potential of quercetin in regulating P. aeruginosa-induced inflammation, with particular emphasized on the interleukin-1? (IL-1?). Our results showed that quercetin exerted the potent inhibitory activity against the production of IL-1? in macrophages infected by live P. aeruginosa PAO1, without exhibiting cytotoxicity. According to our settings, such the potent inhibitory activity of quercetin was clearly demonstrated through its ability to efficiently inhibit IL-1? during P. aeruginosa infection, pre- or even post-infection. In addition, quercetin strongly suppressed MAPK signaling pathway by inhibiting phosphorylation of the p38 MAPK and JNK2, and molecular docking study supported well with this observation. Moreover, quercetin reduced the NLRP3 expression and inhibited the P. aeruginosa-mediated cleavage of caspase-1 as well as mature IL-1?. These results thus indicated that quercetin inhibition of P. aeruginosa-induced IL-1? production is mediated by suppressing the initial priming step and by inhibiting the NLRP3 inflammasome activation. Taken together, our findings demonstrated the promising regulatory activity of quercetin against IL-1? production in P. aeruginosa-infected macrophages, and indicated that quercetin has the potential to be effective as a novel therapeutic agent for treatment of P. aeruginosa-induced inflammation.

Dataset Information

CARD9 negatively regulates NLRP3-induced IL-1? production on Salmonella infection of macrophages.

Publications

CARD9 negatively regulates NLRP3-induced IL-1β production on Salmonella infection of macrophages.

Similar Datasets

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