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

Abstract

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 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 κB suppression and <i>Nlrp3</i> and <i>Il-1</i>β repression. Exaggerated NLRP3 and IL-1β expression in <i>Vsig4^-/-</i> 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-1β suppression, show significant therapeutic efficacy in mouse EAE. These findings highlight VSIG4 as a prospective target for treating NLRP3-associated inflammatory disorders.