RT Journal Article
SR Electronic
T1 Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways
JF ERJ Open Research
JO erjor
FD European Respiratory Society
SP 00474-2022
DO 10.1183/23120541.00474-2022
A1 Nastaran Mues
A1 Richard J. Martin
A1 Rafeul Alam
A1 Niccolette Schaunaman
A1 Kris Genelyn Dimasuay
A1 Christena Kolakowski
A1 Clyde J. Wright
A1 Lijun Zheng
A1 Hong Wei Chu
YR 2022
UL http://openres.ersjournals.com/content/early/2022/10/27/23120541.00474-2022.abstract
AB Background Neutrophilic asthma (NA) is associated with increased airway IL-17 and abnormal bacterial community such as dominance of Nontypeable Haemophilus influenzae (NTHi), particularly during asthma exacerbations. Bacteria release various products including DNA, but whether they cooperate with IL-17 in exaggerating neutrophilic inflammation is unclear. We sought to investigate the role of bacteria-derived DNA in airway neutrophilic inflammation related to IL17-high asthma and underlying mechanisms (e.g., TLR9/IL-36γ signaling axis).Methods Bacterial DNA, IL-8 and IL-36γ were measured in bronchoalveolar lavage fluid (BALF) of asthma and healthy subjects. The role of co-exposure to IL-17 and bacterial DNA or live bacteria in neutrophilic inflammation, and the contribution of the TLR9/IL-36γ signaling axis were determined in cultured primary human airway epithelial cells and alveolar macrophages, and mouse models.Results Bacterial DNA levels were increased in asthma BALF, which positively correlated with IL-8 and neutrophil levels. Moreover, IL-36γ increased in BALF of neutrophilic asthma patients. Bacterial DNA or NTHi infection under an IL-17-high setting amplified IL-8 production and mouse lung neutrophilic inflammation. DNase I treatment in IL-17-exposed and NTHi-infected mouse lungs reduced neutrophilic inflammation. Mechanistically, bacterial DNA-mediated amplification of neutrophilic inflammation is in part depended on the TLR9/IL-36γ signaling axis.Conclusions Bacterial DNA amplifies airway neutrophilic inflammation in an IL-17-high setting partly through the TLR9 and IL-36γ signaling. Our novel findings may offer several potential therapeutic targets including TLR9 antagonists, IL-36γ neutralizing antibodies and DNase I to reduce asthma severity associated with exaggerated airway neutrophilic inflammation.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. 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 the ERJOR online. Please open or download the PDF to view this article.