TLR4 induced Wnt3a-Dvl3 restrains the intensity of inflammation and protects against endotoxin-driven organ failure through GSK3β/β-catenin signaling
| Autor: | Shuang Liang, Junling Ren, Silvia M. Uriarte, Wei Li, Xiaoxian Duan, Dongqiang Yang, Jia Shang, Lan Yakoumatos, Yi Kang, Shujian Li, Huizhi Wang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine Cell signaling Multiple Organ Failure medicine.medical_treatment Immunology Dishevelled Proteins Inflammation Monocytes Article Mice 03 medical and health sciences 0302 clinical medicine Wnt3A Protein medicine Animals Humans Phosphorylation Molecular Biology beta Catenin Glycogen Synthase Kinase 3 beta Tumor Necrosis Factor-alpha Chemistry Transcription Factor RelA Wnt signaling pathway Cell biology Endotoxins Mice Inbred C57BL Toll-Like Receptor 4 030104 developmental biology Cytokine embryonic structures TLR4 Cytokines Tumor necrosis factor alpha medicine.symptom WNT3A Signal Transduction 030215 immunology |
| Zdroj: | Mol Immunol |
| ISSN: | 0161-5890 |
| DOI: | 10.1016/j.molimm.2019.12.013 |
| Popis: | 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 β-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, GSK3β, and β-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 GSK3β-β-catenin signaling and NF-κB activity. General significance Wnt3a-Dvl3-β-catenin signaling axis could be a potential interventional target for manipulating the direction and intensity of inflammatory responses. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect