VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1ß in macrophages.
Sci Adv
; 5(1): eaau7426, 2019 01.
Article
en En
| MEDLINE
| ID: mdl-30662948
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-1ß transcription, caspase-1 activation, pyroptosis, and interleukin-1ß (IL-1ß) 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 Nlrp3 and Il-1ß repression. Exaggerated NLRP3 and IL-1ß 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-1ß suppression, show significant therapeutic efficacy in mouse EAE. These findings highlight VSIG4 as a prospective target for treating NLRP3-associated inflammatory disorders.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transcripción Genética
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Receptores de Complemento
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Interleucina-1beta
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Proteína con Dominio Pirina 3 de la Familia NLR
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Macrófagos
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Sci Adv
Año:
2019
Tipo del documento:
Article