Simone Butz

German Center for Lung Research

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Marcus Mall

Humboldt-Universität zu Berlin

Jolanthe Schatterny

German Center for Lung Research

Johanna J. Salomon

German Center for Lung Research

Heimo Mairbäurl

Heidelberg University

Danny Jonigk

German Center for Lung Research

Simon Y. Graeber

German Center for Lung Research

S Spahn

University of Tübingen

Pamela Millar Büchner

Charité - Universitätsmedizin Berlin

Gesine Hansen

German Center for Lung Research

Olga Halle

Medizinische Hochschule Hannover

Cooperative Institutions

German Center for Lung Research

Heidelberg University

University Hospital Heidelberg

Medizinische Hochschule Hannover

German Cancer Research Center

Epigenomics (Germany)

Heidelberg University

Charité - Universitätsmedizin Berlin

Deutschen Konsortium für Translationale Krebsforschung

DKFZ-ZMBH Alliance

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

European Respiratory Journal (2020)

Matthias Hagner Melanie Albrecht Matteo Guerra Peter Braubach Olga Halle

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.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.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.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.

10.1183/13993003.00716-2019

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Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease

Nature Communications (2021)

Joschka Hey Michelle T. Paulsen Réka Tóth Dieter Weichenhan Simone Butz

Abstract Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focus on the function of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a mouse model of muco-obstructive lung disease ( Scnn1b -transgenic), we identify epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Functionally, AMs from Scnn1b -transgenic mice have reduced efferocytosis and phagocytosis, and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 function and expression. Ex vivo stimulation of wild-type AMs with native mucus impairs efferocytosis and phagocytosis capacities. In addition, mucus induces gene expression changes, comparable with those observed in AMs from Scnn1b -transgenic mice. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.

Reprogramming

efferocytosis

Macrophage polarization

10.1038/s41467-021-26777-9

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Citations (51)

Chronic rhinosinusitis with nasal polyps is associated with impaired TMEM16A-mediated epithelial chloride secretion

Journal of Allergy and Clinical Immunology (2021)

Johanna J. Salomon Tobias Albrecht Simon Y. Graeber Heike Scheuermann Simone Butz

Nasal Polyps

Chronic Rhinosinusitis

10.1016/j.jaci.2021.02.008

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Genetic deletion of the Cl channel Slc26a9 causes airway mucus obstruction and mortality in neonatal mice

03.02 - Airway cell biology and immunopathology (2019)

Johanna J. Salomon Pamela Millar Büchner S Spahn Willi L. Wagner Jolanthe Schatterny

SLC26A9 may serve as an alternative epithelial Cl^- channel in cystic fibrosis (CF) to circumvent impaired CFTR-mediated Cl^- secretion. However, the in vivo role of SLC26A9 in lung development remains unclear. Wild-type (WT) and Slc26a9-deficient (Slc26a9^-/-) mice at neonatal age were investigated for oxygen saturation, histology, inflammatory cell count and cytokine levels. Micro-CT imaging and histology was performed to measure airway mucus obstruction. Transepithelial potential differences (PD) of cultured murine tracheal explants were assessed. The mortality of Slc26a9^-/- mice was significantly increased to 52% compared to WT mice (p<0.05). The oxygen saturation was strongly diminished in Slc26a9^-/- vs. WT mice (p< 0.01). Histological analyses demonstrated an increased mucus volume in the trachea, proximal and distal airways of Slc26a9^-/- mice (p< 0.01). Micro-CT imaging confirmed severe airway mucus obstruction. Functionally, basal PD was decreased in Slc26a9^-/- vs. WT mice (p< 0.05). Levels of IL-1α and IL-1β were significantly augmented (p< 0.01). The inflammatory phenotype was further specified by elevated numbers of neutrophils (p< 0.05) and significantly increased levels of MIP-2 and KC in Slc26a9^-/- mice vs. WT mice (p<0.01). Taken together, Slc26a9^-/- neonates show an early onset of airway mucus obstruction and increased mortality accompanied with neutrophilic inflammation. Our data support that SLC26A9-mediated Cl^- secretion is critical for airway mucus clearance in the neonatal lung and may be a target to modulate the pathogenesis of muco-obstructive lung diseases.

10.1183/13993003.congress-2019.pa4076

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Citations (1)