Abstract
Neutrophilic inflammation in asthma is associated with interleukin (IL)-17A, corticosteroid-insensitivity and bronchodilator-induced forced expiratory volume in 1 s (FEV1) reversibility. IL-17A synergises with tumour necrosis factor (TNF)-α 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-α-induced CXCL-8 production by PBECs from asthma patients.
PBECs from most asthma patients displayed an exaggerated CXCL-8 production in response to TNF-α and IL-17A, but not to TNF-α alone, and which 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. In addition, 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.
Abstract
Defective translational control of neutrophil-driving cytokines in bronchial epithelium leads to exaggerated, corticosteroid-insensitive production in vitro and correlates with neutrophilic inflammation in airway lumen and FEV1 reversibility http://bit.ly/2VrHS2M
Footnotes
This article has supplementary material available from erj.ersjournals.com
Author contributions: A. Ravi conducted experiments, analysed data and prepared the manuscript. S. Chowdhury conducted experiments and analysed data. A. Dijkhuis conducted experiments. P.I. Bonta performed bronchoscopies, established the TASMA study and reviewed the manuscript. P.J. Sterk contributed to study design and reviewed the manuscript. R. Lutter devised the study, contributed to the experimental set-up definition and prepared the manuscript. All authors approved the final version of the manuscript.
Conflict of interest: S. Chowdhury has nothing to disclose.
Conflict of interest: A. Dijkhuis has nothing to disclose.
Conflict of interest: P.I. Bonta has nothing to disclose.
Conflict of interest: P.J. Sterk has nothing to disclose.
Conflict of interest: R. Lutter has nothing to disclose.
Conflict of interest: A. Ravi has nothing to disclose.
Support statement: This study was supported by the Netherlands Asthma Foundation (currently Lung Foundation; projects: 3.2.10.069, 3.2.07.012 and 3.2.06.031) and GSK (CRT 114696). TASMA study: this study is funded by the Netherlands Lung Foundation (grant number: 5.2.13.064JO) and The Netherlands Organization for Health Research and Development (ZonMw grant number: 90713477). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received August 3, 2018.
- Accepted May 10, 2019.
- Copyright ©ERS 2019
INDIVIDUALS
Log in using your username and password
LIBRARY USERS
Log in through your institution
Purchase access
CONTACT US
If you have any questions about the ERS publications website, please contact journals@ersnet.org