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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 <i>Nlrp3</i> and <i>Il-1</i>β 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 <i>Nlrp3</i> remain elusive. We demonstrate here that macrophages lacking V-set and immunoglobulin domain-containing 4 (<i>Vsig4</i>) exhibit significant increases in <i>Nlrp3</i> and <i>Il-1</i>β transcription, caspase-1 activation, pyroptosis, and interleukin-1β (IL-1β) secretion in response to NLRP3 inflammasome stimuli. VSIG4 interacts wi  ...[more]