RT Journal Article
SR Electronic
T1 Neutrophilic inflammation in asthma and defective epithelial translational control
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1900547
DO 10.1183/13993003.00547-2019
VO 54
IS 2
A1 Abilash Ravi
A1 Saheli Chowdhury
A1 Annemiek Dijkhuis
A1 Peter I. Bonta
A1 Peter J. Sterk
A1 René Lutter
YR 2019
UL http://erj.ersjournals.com/content/54/2/1900547.abstract
AB 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.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