TLR3 promotes MMP-9 production in primary human airway epithelial cells through Wnt/\u03b2-catenin signaling

P.-J Royer,The Colt Consortium ,A Roux,C Pison,A Magnan,M Pain,K Henrio,S Brouard,J Loy,A Tissot,P Lacoste

doi:10.1186/s12931-017-0690-y

P.-J Royer, The Colt Consortium + Show 9 more

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https://doi.org/10.1186/s12931-017-0690-y

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Journal: Respiratory research	Publication Date: Dec 1, 2017
Citations: 20	License type: open-access

Affiliation: Nantes Université, Hôpital Foch

Abstract

BackgroundAirway 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.MethodWe 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-β (TGF-β).ResultsWe showed a strong production of pro-inflammatory cytokines (Interleukin (IL)-6, Tumor Necrosis Factor α, TNFα) 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-β 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 β-catenin from the cell membrane and stimulation of the Wnt/β-catenin pathway.ConclusionOur results highlight the cross talk between TGF-β and TLR signaling in bronchial epithelium and its impact on the remodeling process.

Highlights

Airway epithelial cells (AEC) act as the first line of defence in case of lung infections
We showed a strong production of pro-inflammatory cytokines (Interleukin (IL)-6, Tumor Necrosis Factor α, TNFα) or chemokines (CCL2, CCL3, CCL4, CXCL10, CXCL11) by AEC stimulated with poly(I:C)
Our results highlight the cross talk between Transforming Growth Factor-β (TGF-β) and Toll Like Receptor (TLR) signaling in bronchial epithelium and its impact on the remodeling process

Summary

Introduction

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. Disorganisation of airway epithelium is a hallmark of chronic respiratory disorders. Airway remodeling through the process of epithelial to mesenchymal transition (EMT) has been proposed in chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, asthma or chronic lung allograft dysfunction [1,2,3]. Airway epithelium has more than a structural role It is Relationship between remodeling and inflammation has been suggested for a long time [6]. Matrix metalloproteinases (MMP) produced during mesenchymal differentiation spread inflammation through the degradation of matrix and lung tissues, or through the processing of cytokines and chemokines allowing the recruitment of immune cells within the lung [7,8,9]

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