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IL-17A from innate and adaptive lymphocytes contributes to inflammation and damage in cystic fibrosis lung disease

Matthias Hagner, Melanie Albrecht, Matteo Guerra, Peter Braubach, Olga Halle, Zhe Zhou-Suckow, Simone Butz, Danny Jonigk, Gesine Hansen, Carsten Schultz, Anna-Maria Dittrich, Marcus A. Mall
European Respiratory Journal 2021 57: 1900716; DOI: 10.1183/13993003.00716-2019
Matthias Hagner
1Dept of Translational Pulmonology, Translational Lung Research Center (TLRC), University of Heidelberg, Heidelberg, Germany
2German Center for Lung Research (DZL), Germany
10These authors contributed equally to the study
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  • ORCID record for Matthias Hagner
Melanie Albrecht
2German Center for Lung Research (DZL), Germany
3Clinic for Pediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
10These authors contributed equally to the study
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Matteo Guerra
1Dept of Translational Pulmonology, Translational Lung Research Center (TLRC), University of Heidelberg, Heidelberg, Germany
2German Center for Lung Research (DZL), Germany
4Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory, Heidelberg, Germany
5Collaboration for Joint PhD Degree between EMBL and Heidelberg University, Faculty of Biosciences, Heidelberg, Germany
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Peter Braubach
2German Center for Lung Research (DZL), Germany
6Institute for Pathology, Hannover Medical School, Hannover, Germany
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  • ORCID record for Peter Braubach
Olga Halle
2German Center for Lung Research (DZL), Germany
3Clinic for Pediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
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Zhe Zhou-Suckow
1Dept of Translational Pulmonology, Translational Lung Research Center (TLRC), University of Heidelberg, Heidelberg, Germany
2German Center for Lung Research (DZL), Germany
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Simone Butz
1Dept of Translational Pulmonology, Translational Lung Research Center (TLRC), University of Heidelberg, Heidelberg, Germany
2German Center for Lung Research (DZL), Germany
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Danny Jonigk
2German Center for Lung Research (DZL), Germany
6Institute for Pathology, Hannover Medical School, Hannover, Germany
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Gesine Hansen
2German Center for Lung Research (DZL), Germany
3Clinic for Pediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
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Carsten Schultz
2German Center for Lung Research (DZL), Germany
4Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory, Heidelberg, Germany
7Dept of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, USA
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Anna-Maria Dittrich
2German Center for Lung Research (DZL), Germany
3Clinic for Pediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
11These authors contributed equally as senior authors
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Marcus A. Mall
1Dept of Translational Pulmonology, Translational Lung Research Center (TLRC), University of Heidelberg, Heidelberg, Germany
2German Center for Lung Research (DZL), Germany
8Dept of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
9Berlin Institute of Health (BIH), Berlin, Germany
11These authors contributed equally as senior authors
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  • For correspondence: marcus.mall@charite.de
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Abstract

Background Elevated levels of interleukin (IL)-17A were detected in the airways of patients with cystic fibrosis (CF), but its cellular sources and role in the pathogenesis of CF lung disease remain poorly understood. The aim of this study was to determine the sources of IL-17A and its role in airway inflammation and lung damage in CF.

Methods We performed flow cytometry to identify IL-17A-producing cells in lungs and peripheral blood from CF patients and β-epithelial Na+ channel transgenic (Scnn1b-Tg) mice with CF-like lung disease, and determined the effects of genetic deletion of Il17a and Rag1 on the pulmonary phenotype of Scnn1b-Tg mice.

Results T-helper 17 cells, CD3+CD8+ T-cells, γδ T-cells, invariant natural killer T-cells and innate lymphoid cells contribute to IL-17A secretion in lung tissue, lymph nodes and peripheral blood of patients with CF. Scnn1b-Tg mice displayed increased pulmonary expression of Il17a and elevated IL-17A-producing innate and adaptive lymphocytes with a major contribution by γδ T-cells. Lack of IL-17A, but not the recombination activating protein RAG1, reduced neutrophilic airway inflammation in Scnn1b-Tg mice. Genetic deletion of Il17a or Rag1 had no effect on mucus obstruction, but reduced structural lung damage and revealed an IL-17A-dependent macrophage activation in Scnn1b-Tg mice.

Conclusions We identify innate and adaptive sources of IL-17A in CF lung disease. Our data demonstrate that IL-17A contributes to airway neutrophilia, macrophage activation and structural lung damage in CF-like lung disease in mice. These results suggest IL-17A as a novel target for anti-inflammatory therapy of CF lung disease.

Abstract

IL-17A is produced by innate and adaptive lymphocytes in lungs from patients with CF, and contributes to neutrophilic airway inflammation and structural lung damage in mice with CF-like lung disease https://bit.ly/339G45c

Footnotes

  • This article has supplementary material available from erj.ersjournals.com

  • Conflict of interest: M. Hagner has nothing to disclose.

  • Conflict of interest: M. Albrecht has nothing to disclose.

  • Conflict of interest: M. Guerra has nothing to disclose.

  • Conflict of interest: P. Braubach has nothing to disclose.

  • Conflict of interest: O. Halle has nothing to disclose.

  • Conflict of interest: Z. Zhou-Suckow has nothing to disclose.

  • Conflict of interest: S. Butz has nothing to disclose.

  • Conflict of interest: D. Jonigk has nothing to disclose.

  • Conflict of interest: G. Hansen has nothing to disclose.

  • Conflict of interest: C. Schultz reports personal fees for consultancy and is a shareholder in SiChem GmbH, outside the submitted work.

  • Conflict of interest: A-M. Dittrich has nothing to disclose.

  • Conflict of interest: M.A. Mall reports grants from the German Federal Ministry of Education and Research (82DZL00401 and 82DZL004A1) and Einstein Foundation Berlin (EP-2017-393), during the conduct of the study; personal fees for advisory board work and consultancy from Spyryx Biosciences, Boehringer Ingelheim, Polyphor and Santhera, personal fees for advisory board work from ProQR, PTC Pharmaceuticals, Arrowhead and Pro Axis, personal fees for consultancy and lectures from Bayer, personal fees for consultancy from Enterprise Therapeutics and Sterna Biologicals, personal fees for advisory board work, lectures and consultancy from Vertex Pharmaceuticals, outside the submitted work; and has a patent on the Scnn1b-Tg mouse with royalties paid.

  • Support statement: Supported by grants from the German Ministry for Education and Research (82DZL004A1 to M.A. Mall and 82DZL002A1 to G. Hansen), the German Research Foundation (SFB-TR84TP B08 to M.A. Mall and PP1937TP to A-M. Dittrich), the Mukoviszidose Institut gGmbH Bonn, the research and development arm of the German Cystic Fibrosis Association Mukoviszidose eV (project number 1604 to M. Albrecht), and the Einstein Foundation Berlin (EP-2017-393 to M.A. Mall). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received April 8, 2019.
  • Accepted November 15, 2020.
  • Copyright ©ERS 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
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IL-17A from innate and adaptive lymphocytes contributes to inflammation and damage in cystic fibrosis lung disease
Matthias Hagner, Melanie Albrecht, Matteo Guerra, Peter Braubach, Olga Halle, Zhe Zhou-Suckow, Simone Butz, Danny Jonigk, Gesine Hansen, Carsten Schultz, Anna-Maria Dittrich, Marcus A. Mall
European Respiratory Journal Jun 2021, 57 (6) 1900716; DOI: 10.1183/13993003.00716-2019

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IL-17A from innate and adaptive lymphocytes contributes to inflammation and damage in cystic fibrosis lung disease
Matthias Hagner, Melanie Albrecht, Matteo Guerra, Peter Braubach, Olga Halle, Zhe Zhou-Suckow, Simone Butz, Danny Jonigk, Gesine Hansen, Carsten Schultz, Anna-Maria Dittrich, Marcus A. Mall
European Respiratory Journal Jun 2021, 57 (6) 1900716; DOI: 10.1183/13993003.00716-2019
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