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The NLRP3 inflammasome modulates glycolysis by increasing PFKFB3 in an IL-1?-dependent manner in macrophages.

ABSTRACT: Inflammation and metabolism are intricately linked during inflammatory diseases in which activation of the nucleotide-binding domain-like receptors Family Pyrin Domain Containing 3 (NLRP3) inflammasome, an innate immune sensor, is critical. Several factors can activate the NLRP3 inflammasome, but the nature of the link between NLRP3 inflammasome activation and metabolism remains to be thoroughly explored. This study investigates whether the small molecule inhibitor of the NLRP3 inflammasome, MCC950, modulates the lipopolysaccharide (LPS) -and amyloid-? (A?)-induced metabolic phenotype and inflammatory signature in macrophages. LPS?+?A? induced IL-1? secretion, while pre-treatment with MCC950 inhibited this. LPS?+?A? also upregulated IL-1? mRNA and supernatant concentrations of TNF?, IL-6 and IL-10, however these changes were insensitive to MCC950, confirming that MCC950 specifically targets inflammasome activation in BMDMs. LPS?+?A? increased glycolysis and the glycolytic enzyme, PFKFB3, and these effects were decreased by MCC950. These findings suggest that NLRP3 inflammasome activation may play a role in modulating glycolysis. To investigate this further, the effect of IL-1? on glycolysis was assessed. IL-1? stimulated glycolysis and PFKFB3, mimicking the effect of LPS?+?A? and adding to the evidence that inflammasome activation impacts on metabolism. This contention was supported by the finding that the LPS?+?A?-induced changes in glycolysis and PFKFB3 were attenuated in BMDMs from NLRP3-deficient and IL-1R1-deficient mice. Consistent with a key role for PFKFB3 is the finding that the PFKFB3 inhibitor, 3PO, attenuated the LPS?+?A?-induced glycolysis. The data demonstrate that activation of the NLRP3 inflammasome, and the subsequent release of IL-1?, play a key role in modulating glycolysis via PFKFB3. Reinstating metabolic homeostasis by targeting the NLRP3 inflammasome-PFKFB3 axis may provide a novel therapeutic target for treatment of acute and chronic disease.

SUBMITTER: Finucane OM

PROVIDER: S-EPMC6411754 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The NLRP3 inflammasome modulates glycolysis by increasing PFKFB3 in an IL-1β-dependent manner in macrophages.

Finucane Orla M OM Sugrue Jamie J Rubio-Araiz Ana A Guillot-Sestier Marie-Victoire MV Lynch Marina A MA

Scientific reports 20190311 1

Inflammation and metabolism are intricately linked during inflammatory diseases in which activation of the nucleotide-binding domain-like receptors Family Pyrin Domain Containing 3 (NLRP3) inflammasome, an innate immune sensor, is critical. Several factors can activate the NLRP3 inflammasome, but the nature of the link between NLRP3 inflammasome activation and metabolism remains to be thoroughly explored. This study investigates whether the small molecule inhibitor of the NLRP3 inflammasome, MCC ...[more]

PMID: 30858427

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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.

Dataset Information

The NLRP3 inflammasome modulates glycolysis by increasing PFKFB3 in an IL-1?-dependent manner in macrophages.

Publications

The NLRP3 inflammasome modulates glycolysis by increasing PFKFB3 in an IL-1β-dependent manner in macrophages.

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