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

International audienceBACKGROUND: 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

Altered pIgR/IgA mucosal immunity in bronchiolitis obliterans syndrome

Aims: Long-term survival after lung transplantation (LT) is hampered by the occurrence of chronic lung allograft dysfunction (CLAD), manifesting as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). CLAD is triggered by several factors, e.g. recurrent infections. As immunoglobulin (Ig) A is crucial to ensure mucosal immunity and limit airway microbial load, we explored whether IgA and its epithelial receptor, the polymeric Ig receptor (pIgR) are impaired in BOS. Methods: Bronchoalveolar lavages (BAL, n=120) from LT recipients included in the Cohort for Lung Transplantation were collected at pre-defined timepoints prior to the diagnosis of functional stability (BOS-free, n=30) or BOS (pre-BOS, n=30), and assessed for secretory (S)-IgA. Bronchiolar epithelium pIgR expression was quantified in transbronchial biopsies from BOS-free (n=20), pre-BOS (n=19) and BOS LT recipients (n=12), as well as in end-stage BOS explants (n=15). Results: S-IgA levels were reduced in BAL from pre-BOS LT recipients versus BOS-free (16.1 vs 33.4 µg/ml, p<0.01). pIgR bronchiolar expression was reduced in transbronchial biopsies from BOS (p<0.05 vs BOS-free and pre-BOS), with further decrease in end-stage BOS explants (p<0.0001 vs BOS-free and pre-BOS). Conclusions: BAL S-IgA and pIgR decreased levels suggest that the pIgR/IgA system is impaired in BOS. This could play a pathogenic role by increasing susceptibility to local infections

Blood MMP-9 measured at 2 years after lung transplantation as a prognostic biomarker of chronic lung allograft dysfunction

Abstract Background Long-term outcomes of lung transplantation (LTx) remain hampered by chronic lung allograft dysfunction (CLAD). Matrix metalloproteinase 9 (MMP-9) is a secretory endopeptidase identified as a key mediator in fibrosis processes associated with CLAD. The objective of this study was to investigate whether plasma MMP9 levels may be prognostic of CLAD development. Methods Participants were selected from the Cohort in Lung Transplantation (COLT) for which a biocollection was associated. We considered two time points, year 1 (Y1) and year 2 (Y2) post-transplantation, for plasma MMP-9 measurements. We analysed stable recipients at those time points, comparing those who would develop a CLAD within the 2 years following the measurement to those who would remain stable 2 years after. Results MMP-9 levels at Y1 were not significantly different between the CLAD and stable groups (230 ng/ml vs. 160 ng/ml, p = 0.4). For the Y2 analysis, 129 recipients were included, of whom 50 developed CLAD within 2 years and 79 remained stable within 2 years. MMP-9 plasma median concentrations were higher in recipients who then developed CLAD than in the stable group (230 ng/ml vs. 118 ng/ml, p = 0.003). In the multivariate analysis, the Y2 MMP-9 level was independently associated with CLAD, with an average increase of 150 ng/ml (95% CI [0–253], p = 0.05) compared to that in the stable group. The Y2 ROC curve revealed a discriminating capacity of blood MMP-9 with an area under the curve of 66%. Conclusion Plasmatic MMP-9 levels measured 2 years after lung transplantation have prognostic value for CLAD