Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways
Background Neutrophilic asthma (NA) is associated with increased airway interleukin (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 coo...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
European Respiratory Society
2023-01-01
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| Series: | ERJ Open Research |
| Online Access: | http://openres.ersjournals.com/content/9/1/00474-2022.full |
| _version_ | 1797809426038521856 |
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| author | Nastaran Mues Richard J. Martin Rafeul Alam Niccolette Schaunaman Kris Genelyn Dimasuay Christena Kolakowski Clyde J. Wright Lijun Zheng Hong Wei Chu |
| author_facet | Nastaran Mues Richard J. Martin Rafeul Alam Niccolette Schaunaman Kris Genelyn Dimasuay Christena Kolakowski Clyde J. Wright Lijun Zheng Hong Wei Chu |
| author_sort | Nastaran Mues |
| collection | DOAJ |
| description | Background
Neutrophilic asthma (NA) is associated with increased airway interleukin (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 IL-17-high asthma and underlying mechanisms (e.g. Toll-like receptor 9 (TLR9)/IL-36γ signalling axis).
Methods
Bacterial DNA, IL-8 and IL-36γ were measured in bronchoalveolar lavage fluid (BALF) of people with 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 signalling 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 NA 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 dependent on the TLR9/IL-36γ signalling axis.
Conclusions
Bacterial DNA amplifies airway neutrophilic inflammation in an IL-17-high setting partly through the TLR9 and IL-36γ signalling axis. Our novel findings may offer several potential therapeutic targets including TLR9 antagonists, IL-36γ neutralising antibodies and DNase I to reduce asthma severity associated with exaggerated airway neutrophilic inflammation. |
| first_indexed | 2024-03-13T06:52:33Z |
| format | Article |
| id | doaj.art-474caab9c4564a6d811312a57cb6b93c |
| institution | Directory Open Access Journal |
| issn | 2312-0541 |
| language | English |
| last_indexed | 2024-03-13T06:52:33Z |
| publishDate | 2023-01-01 |
| publisher | European Respiratory Society |
| record_format | Article |
| series | ERJ Open Research |
| spelling | doaj.art-474caab9c4564a6d811312a57cb6b93c2023-06-07T13:30:44ZengEuropean Respiratory SocietyERJ Open Research2312-05412023-01-019110.1183/23120541.00474-202200474-2022Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airwaysNastaran Mues0Richard J. Martin1Rafeul Alam2Niccolette Schaunaman3Kris Genelyn Dimasuay4Christena Kolakowski5Clyde J. Wright6Lijun Zheng7Hong Wei Chu8 Department of Medicine, National Jewish Health, Denver, CO, USA Department of Medicine, National Jewish Health, Denver, CO, USA Department of Medicine, National Jewish Health, Denver, CO, USA Department of Medicine, National Jewish Health, Denver, CO, USA Department of Medicine, National Jewish Health, Denver, CO, USA Department of Medicine, National Jewish Health, Denver, CO, USA Department of Pediatrics, Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO, USA Department of Pediatrics, Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO, USA Department of Medicine, National Jewish Health, Denver, CO, USA Background Neutrophilic asthma (NA) is associated with increased airway interleukin (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 IL-17-high asthma and underlying mechanisms (e.g. Toll-like receptor 9 (TLR9)/IL-36γ signalling axis). Methods Bacterial DNA, IL-8 and IL-36γ were measured in bronchoalveolar lavage fluid (BALF) of people with 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 signalling 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 NA 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 dependent on the TLR9/IL-36γ signalling axis. Conclusions Bacterial DNA amplifies airway neutrophilic inflammation in an IL-17-high setting partly through the TLR9 and IL-36γ signalling axis. Our novel findings may offer several potential therapeutic targets including TLR9 antagonists, IL-36γ neutralising antibodies and DNase I to reduce asthma severity associated with exaggerated airway neutrophilic inflammation.http://openres.ersjournals.com/content/9/1/00474-2022.full |
| spellingShingle | Nastaran Mues Richard J. Martin Rafeul Alam Niccolette Schaunaman Kris Genelyn Dimasuay Christena Kolakowski Clyde J. Wright Lijun Zheng Hong Wei Chu Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways ERJ Open Research |
| title | Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways |
| title_full | Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways |
| title_fullStr | Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways |
| title_full_unstemmed | Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways |
| title_short | Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways |
| title_sort | bacterial dna amplifies neutrophilic inflammation in il 17 exposed airways |
| url | http://openres.ersjournals.com/content/9/1/00474-2022.full |
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