Dataset Information

VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1? in macrophages.

ABSTRACT: Hyperactivation of the NLRP3 inflammasome contributes to the pathogenesis of multiple diseases, but the mechanisms underlying transcriptional regulation of Nlrp3 remain elusive. We demonstrate here that macrophages lacking V-set and immunoglobulin domain-containing 4 (Vsig4) exhibit significant increases in Nlrp3 and Il-1? transcription, caspase-1 activation, pyroptosis, and interleukin-1? (IL-1?) secretion in response to NLRP3 inflammasome stimuli. VSIG4 interacts with MS4A6D in the formation of a surface signaling complex. VSIG4 occupancy triggers Ser232 and Ser235 phosphorylation in MS4A6D, leading to activation of JAK2-STAT3-A20 cascades that further results in nuclear factor ?B suppression and Nlrp3 and Il-1? repression. Exaggerated NLRP3 and IL-1? expression in Vsig4-/- mice is accountable for deleterious disease severity in experimental autoimmune encephalomyelitis (EAE) and resistance to dextran sulfate sodium (DSS)-induced colitis. The agonistic VSIG4 antibodies (VG11), acting through NLRP3 and IL-1? suppression, show significant therapeutic efficacy in mouse EAE. These findings highlight VSIG4 as a prospective target for treating NLRP3-associated inflammatory disorders.

SUBMITTER: Huang X

PROVIDER: S-EPMC6326752 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1β in macrophages.

Huang Xiaoyong X Feng Zeqing Z Jiang Yuanzhong Y Li Jialin J Xiang Qun Q Guo Sheng S Yang Chengying C Fei Lei L Guo Guoning G Zheng Lixin L Wu Yuzhang Y Chen Yongwen Y

Science advances 20190109 1

Hyperactivation of the NLRP3 inflammasome contributes to the pathogenesis of multiple diseases, but the mechanisms underlying transcriptional regulation of Nlrp3 remain elusive. We demonstrate here that macrophages lacking V-set and immunoglobulin domain-containing 4 (Vsig4) exhibit significant increases in Nlrp3 and Il-1β transcription, caspase-1 activation, pyroptosis, and interleukin-1β (IL-1β) secretion in response to NLRP3 inflammasome stimuli. VSIG4 interacts wi ...[more]

PMID: 30662948

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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

VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1? in macrophages.

Publications

VSIG4 mediates transcriptional inhibition of <i>Nlrp3</i> and <i>Il-1</i>β in macrophages.

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