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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-1β (IL-1β). Our results showed that quercetin exerted the potent inhibitory activity against the production of IL-1β 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-1β 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-1β. These results thus indicated that quercetin inhibition of P. aeruginosa-induced IL-1β 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-1β 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.

Project description:Macrophages are immune cells of hematopoietic origin that play diverse roles in host defenses and tissue homeostasis. In mechanical microenvironments, macrophages receive mechanical signals that regulate various cellular functions. However, the mechanisms by which mechanical signals influence the phenotype and function of macrophages in the process of inflammation have not yet been elucidated in detail. We herein examined the effects of cyclic stretch (CS) on NLR family, pyrin domain-containing 3 (NLRP3) inflammasome activation in J774.1, a murine macrophage cell line, and mouse primary bone marrow-derived macrophages. We showed that cyclic stretch inhibited adenosine triphosphate (ATP)-stimulated interleukin (IL)-1β secretion in lipopolysaccharide (LPS)-primed macrophages using ELISA and Western blot analyses. Cyclic stretch did not affect the degradation of the Inhibitor of κB or the nuclear translocation/transcriptional activity of nuclear factor (NF)-κB, suggesting that cyclic stretch-mediated inhibition was independent of the NF-κB signaling pathway. Consistent with these results, cyclic stretch did not affect the LPS-induced expression of inflammasome components, such as pro-IL-1β and NLRP3, which is known to require the activation of NF-κB signaling. We showed that the cyclic stretch-mediated inhibition of IL-1β secretion was caused by the suppression of caspase-1 activity. The addition of compound C, a specific inhibitor of adenosine monophosphate-activated protein kinase (AMPK), to LPS-primed macrophages inhibited IL-1β secretion as well as caspase-1 activation, suggesting that AMPK signaling is involved in ATP-triggered IL-1β secretion. Furthermore, the phosphorylation of AMPK induced by ATP in LPS-primed macrophages was significantly suppressed by cyclic stretch, indicating that cyclic stretch negatively regulates IL-1β secretion through the inhibition of caspase-1 activity by attenuating the AMPK pathway. Our results suggest that mechanical stress functions to maintain homeostasis through the prevention of excessive inflammasome activation in macrophages in mechanical microenvironments.

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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