Neutrophilic inflammation in asthma and defective epithelial translational control
AbilashÂ Ravi,Â SaheliÂ Chowdhury,Â AnnemiekÂ Dijkhuis,Â Peter I.Â Bonta,Â Peter J.Â Sterk,Â RenÃ©Â Lutter
European Respiratory JournalÂ 2019;Â DOI:Â 10.1183/13993003.00547-2019
Neutrophilic inflammation in asthma is associated with interleukin-17A (IL-17A), corticosteroid-insensitivity and bronchodilator-induced FEV1Â reversibility. IL-17A synergizes with tumour necrosis factor-Î± (TNF-Î±) in the production of the neutrophil chemokine CXCL-8 by primary bronchial epithelial cells (PBECs).
We hypothesised that local neutrophilic inflammation in asthma correlates with IL-17A and TNF-Î±-induced CXCL-8 production by PBECs from asthma patients.
PBECs from most asthma patients displayed an exaggerated CXCL-8 production to TNF-Î± and IL-17A, but not to TNF-Î± alone, and that was also insensitive to corticosteroids. This hyperresponsiveness of PBECs strongly correlated with CXCL-8 levels and neutrophil numbers in bronchoalveolar lavage from the corresponding patients, but not with that of eosinophils. This hyperresponsiveness also correlated with bronchodilator-induced FEV1% reversibility. At the molecular level epithelial hyperresponsiveness was associated with failure of the translational repressor T-cell internal antigen-1 related protein (TiAR) to translocate to the cytoplasm to halt CXCL-8 production, as confirmed by TiAR knockdown. This is in line with the finding that hyperresponsive PBECs also produced enhanced levels of other inflammatory mediators.
Hyperresponsive PBECs in asthma patients may underlie neutrophilic and corticosteroid-insensitive inflammation and a reduced FEV1, irrespective of eosinophilic inflammation. Normalising cytoplasmic translocation of TiAR is a potential therapeutic target in neutrophilic, corticosteroid-insensitive asthma.
This manuscript has recently been accepted for publication in theÂ European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of theÂ ERJÂ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Ravi has nothing to disclose.
Conflict of interest: Dr. Chowdhury has nothing to disclose.
Conflict of interest: Dr. Dijkhuis has nothing to disclose.
Conflict of interest: Dr. Bonta has nothing to disclose.
Conflict of interest: Dr. Sterk has nothing to disclose.
Conflict of interest: Dr. Lutter has nothing to disclose.
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