| First Author | Huang X | Year | 2019 |
| Journal | Sci Adv | Volume | 5 |
| Issue | 1 | Pages | eaau7426 |
| PubMed ID | 30662948 | Mgi Jnum | J:281762 |
| Mgi Id | MGI:6359081 | Doi | 10.1126/sciadv.aau7426 |
| Citation | Huang X, et al. (2019) VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1beta in macrophages. Sci Adv 5(1):eaau7426 |
| abstractText | 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-1beta transcription, caspase-1 activation, pyroptosis, and interleukin-1beta (IL-1beta) secretion in response to NLRP3 inflammasome stimuli. VSIG4 interacts with MS4A6D in the formation of a surface signaling complex. VSIG4 occupancy triggers Ser(232) and Ser(235) phosphorylation in MS4A6D, leading to activation of JAK2-STAT3-A20 cascades that further results in nuclear factor kappaB suppression and Nlrp3 and Il-1beta repression. Exaggerated NLRP3 and IL-1beta 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-1beta suppression, show significant therapeutic efficacy in mouse EAE. These findings highlight VSIG4 as a prospective target for treating NLRP3-associated inflammatory disorders. |
