TLR4 induced Wnt3a-Dvl3 restrains the intensity of inflammation and protects against endotoxin-driven organ failure through GSK3ß/ß-catenin signaling.
Mol Immunol
; 118: 153-164, 2020 02.
Article
em En
| MEDLINE
| ID: mdl-31884387
ABSTRACT
BACKGROUND:
Accumulating evidence suggests a regulatory role of Wnt proteins in innate immune responses. However, the effects of Wnt3a signaling on TLR4-mediated inflammatory responses are controversial and the signaling crosstalk between TLR4 and Wnt3a remains uncertain.METHODS:
Gain- and Loss- of function approaches were utilized to determine the function of Wnt3a signaling in TLR4-mediated inflammatory responses. Cytokine production at protein and mRNA levels and phosphorylation of signaling molecules were measured by ELISA, qRT-PCR, and Western Blot, respectively. Endotoxemia mouse model was employed to assess the effect of Wnt3a on systemic inflammatory cytokine levels and neutrophil infiltration.RESULTS:
LPS stimulation leads to an increase of Wnt3a expression and its downstream molecule, Dvl3, in primary monocytes. Inhibition or silence of Wnt3a or Dvl3 significantly increases the production of pro-inflammatory cytokines (IL-12, IL-6, TNFα), robustly reduces ß-catenin accumulation, and enhances the phosphorylation of NF-κB P65 and its DNA binding activity. These results were confirmed by multiple gain- and loss- of function approaches including specific siRNA and ectopic expression of Dvl3, GSK3ß, and ß-catenin in monocytes. Moreover, in vivo relevance was established in a murine endotoxin model, in which Wnt3a inhibition enhances the inflammatory responses by augmenting the systemic pro-inflammatory cytokine levels and neutrophil infiltration.CONCLUSIONS:
TLR4 activation promotes Wnt3a-Dvl3 signaling, which acts as rheostats to restrain the intensity of inflammation through regulating GSK3ß-ß-catenin signaling and NF-κB activity. GENERALSIGNIFICANCE:
Wnt3a-Dvl3-ß-catenin signaling axis could be a potential interventional target for manipulating the direction and intensity of inflammatory responses.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Beta Catenina
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Receptor 4 Toll-Like
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Proteína Wnt3A
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Glicogênio Sintase Quinase 3 beta
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Proteínas Desgrenhadas
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Inflamação
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article