TLR3 promotes MMP-9 production in primary human airway epithelial cells through Wnt/beta-catenin signaling.

Abstract : BACKGROUND: Airway epithelial cells (AEC) act as the first line of defence in case of lung infections. They constitute a physical barrier against pathogens and they participate in the initiation of the immune response. Yet, the modalities of pathogen recognition by AEC and the consequences on the epithelial barrier remain poorly documented. METHOD: We investigated the response of primary human AEC to viral (polyinosinic-polycytidylic acid, poly(I:C)) and bacterial (lipopolysaccharide, LPS) stimulations in combination with the lung remodeling factor Transforming Growth Factor-beta (TGF-beta). RESULTS: We showed a strong production of pro-inflammatory cytokines (Interleukin (IL)-6, Tumor Necrosis Factor alpha, TNFalpha) or chemokines (CCL2, CCL3, CCL4, CXCL10, CXCL11) by AEC stimulated with poly(I:C). Cytokine and chemokine production, except CXCL10, was Toll Like Receptor (TLR)-3 dependent and although they express TLR4, we found no cytokine production after LPS stimulation. Poly(I:C), but not LPS, synergised with TGF-beta for the production of matrix metalloproteinase-9 (MMP-9) and fibronectin. Mechanistic analyses suggest the secretion of Wnt ligands by AEC along with a degradation of the cellular junctions after poly(I:C) exposure, leading to the release of beta-catenin from the cell membrane and stimulation of the Wnt/beta-catenin pathway. CONCLUSION: Our results highlight the cross talk between TGF-beta and TLR signaling in bronchial epithelium and its impact on the remodeling process.
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Pierre-Joseph Royer, Kelly Henrio, Mallaury Pain, Jennifer Loy, Antoine Roux, et al.. TLR3 promotes MMP-9 production in primary human airway epithelial cells through Wnt/beta-catenin signaling.. Respiratory Research, BioMed Central, 2017, 18 (1), pp.208. ⟨10.1186/s12931-017-0690-y⟩. ⟨inserm-01885568⟩

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