VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1β in macrophages
VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1β in macrophages
复制标题
VSIG4 介导巨噬细胞中 Nlrp3 和 Il-1β 的转录抑制
DOI：
10.1126/sciadv.aau7426
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发表时间：
2019-01-01
期刊：
影响因子：
13.6
通讯作者：
Chen, Yongwen
中科院分区：
文献类型：
--
作者：
Huang, Xiaoyong;Feng, Zeqing;Chen, Yongwen
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 beta transcription, caspase-1 activation, pyroptosis, and interleukin-1 beta (IL-1 beta) 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 kappa B suppression and Nlrp3 and Il-1 beta repression. Exaggerated NLRP3 and IL-1 beta 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 beta suppression, show significant therapeutic efficacy in mouse EAE. These findings highlight VSIG4 as a prospective target for treating NLRP3-associated inflammatory disorders.
