Immune Training of the Interleukin 6 Gene in Airway Epithelial Cells is Central to Asthma Exacerbations

Lars P Lunding^{1

2}, Markus Weckmann^{2

3

4}, Ulrich M Zissler^{5

6

7}, Constanze Jakwerth^{5

8}, Rebecca Bodenstein-Sgró^{1

2}, Sina Webering^{1

2}, Christina Vock^{2

9}, Johanna C Ehlers^{2

9}, Romina A M Fernandez Ceballos^{2

3}, Sai Sneha Priya Nemani^{2

3}, Karosham Diren Reddy^{2

3

4}, Brian George G Oliver^{10

11}, Cornelis J Vermeulen¹², Maarten van de Berge¹², Carole Ober¹³, Axel Künstner¹⁴, Hauke Busch¹⁵, Inke König^{2

16}, Christoph Garbers¹⁷, Carsten B Schmidt-Weber^{5

8}, Marcel F Nold^{18

19

20}, Ali Önder Yildirim^{6

21}, Claudia A Nold-Petry^{18

19}, Zane Orinska^{2

22}, Thomas Bahmer^{2

23}, Jan Heyckendorf^{2

6

23}, Gesine Hansen^{24

25}, Erika von Mutius^{6

26

27}, Klaus F Rabe^{2

23

28}, Anna-Maria Dittrich^{24

25}, Bianca Schaub^{8

27}, Folke Brinkmann^{2

3}, Matthias V Kopp^{2

3

29}, Michael Wegmann^{1

2}; ALLIANCE Study Group as part of the German Centre for Lung Research (DZL)

Affiliations

¹ Division of Lung Immunology, Priority Area Chronic Lung Diseases, Research Centre Borstel - Leibniz Lung Centre, Borstel, Germany.
² Airway Research Centre North, Member of the German Centre for Lung Research (DZL), Germany.
³ Department of Paediatric Pneumology & Allergology, University Clinics Schleswig-Holstein (UKSH), Lübeck, Germany.
⁴ Division of Epigenetics of Chronic Lung Diseases, Priority Area Chronic Lung Diseases, Research Centre Borstel - Leibniz Lung Centre, Borstel, Germany.
⁵ Centre of Allergy and Environment (ZAUM), Technische Universität and Helmholtz Centre Munich, Munich, Germany.
⁶ Technology Transfer Center for Building Biology and Indoor Health, Rosenheim Technical University of Applied Sciences, Freilassing, Germany.
⁷ Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC), Marburg, Germany.
⁸ Comprehensive Pneumology Centre Munich (CPC-M), Member of the German Centre for Lung Research (DZL), Germany.
⁹ Division of Experimental Pneumology, Priority Area Chronic Lung Diseases, Research Centre Borstel- Leibniz Lung Centre, Borstel, Germany.
¹⁰ School of Medical and Molecular Biosciences, University of Technology Sydney, Australia.
¹¹ Woolcock Institute of Medical Research, The University of Sydney, Australia.
¹² University Medical Centre Groningen, Department of Pulmonary Diseases, GRIAC, the Netherlands.
¹³ Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
¹⁴ Luebeck Institute of Experimental Dermatology and Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany.
¹⁵ Luebeck Institute of Experimental Dermatology, Institute for Cardiogenetics and Centre for Research of Inflammatory Skin Disease (CRIS), University of Luebeck, Luebeck, Germany.
¹⁶ Institute for Medical Biometry and Statistics, University of Luebeck, Luebeck, Germany.
¹⁷ Instititute for Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
¹⁸ Department of Paediatrics, Monash University, Melbourne, Victoria, Australia.
¹⁹ Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.
²⁰ Monash Newborn, Monash Children's Hospital, Melbourne, Victoria, Australia.
²¹ Institute of Lung Biology and Disease, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany.
²² Division of Immunology and Cell Biology, Priority Area Chronic Lung Diseases, Research Centre Borstel - Leibniz Lung Centre, Borstel, Germany.
²³ University Hospital Schleswig-Holstein Campus Kiel, Department for Internal Medicine I, Kiel, Germany.
²⁴ Translational Paediatric Pneumology, Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
²⁵ Biomedical Research in End Stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre of Lung Research (DZL), Germany.
²⁶ Institute for Asthma and Allergy Prevention, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany.
²⁷ Dr. von Hauner University Children's Hospital of Ludwig Maximilian's University, Munich, Germany.
²⁸ Department of Pneumology, LungenClinic Grosshansdorf, Grosshansdorf, Germany.
²⁹ Department of Paediatric Respiratory Medicine, Inselspital, University Children's Hospital of Bern, University of Bern, Bern, Switzerland.

PMID: 41099307
DOI: 10.1111/all.70070

Immune Training of the Interleukin 6 Gene in Airway Epithelial Cells is Central to Asthma Exacerbations

Lars P Lunding et al. Allergy. 2025.

. 2025 Oct 16.

doi: 10.1111/all.70070. Online ahead of print.

Authors

Affiliations

¹ Division of Lung Immunology, Priority Area Chronic Lung Diseases, Research Centre Borstel - Leibniz Lung Centre, Borstel, Germany.
² Airway Research Centre North, Member of the German Centre for Lung Research (DZL), Germany.
³ Department of Paediatric Pneumology & Allergology, University Clinics Schleswig-Holstein (UKSH), Lübeck, Germany.
⁴ Division of Epigenetics of Chronic Lung Diseases, Priority Area Chronic Lung Diseases, Research Centre Borstel - Leibniz Lung Centre, Borstel, Germany.
⁵ Centre of Allergy and Environment (ZAUM), Technische Universität and Helmholtz Centre Munich, Munich, Germany.
⁶ Technology Transfer Center for Building Biology and Indoor Health, Rosenheim Technical University of Applied Sciences, Freilassing, Germany.
⁷ Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC), Marburg, Germany.
⁸ Comprehensive Pneumology Centre Munich (CPC-M), Member of the German Centre for Lung Research (DZL), Germany.
⁹ Division of Experimental Pneumology, Priority Area Chronic Lung Diseases, Research Centre Borstel- Leibniz Lung Centre, Borstel, Germany.
¹⁰ School of Medical and Molecular Biosciences, University of Technology Sydney, Australia.
¹¹ Woolcock Institute of Medical Research, The University of Sydney, Australia.
¹² University Medical Centre Groningen, Department of Pulmonary Diseases, GRIAC, the Netherlands.
¹³ Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
¹⁴ Luebeck Institute of Experimental Dermatology and Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany.
¹⁵ Luebeck Institute of Experimental Dermatology, Institute for Cardiogenetics and Centre for Research of Inflammatory Skin Disease (CRIS), University of Luebeck, Luebeck, Germany.
¹⁶ Institute for Medical Biometry and Statistics, University of Luebeck, Luebeck, Germany.
¹⁷ Instititute for Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
¹⁸ Department of Paediatrics, Monash University, Melbourne, Victoria, Australia.
¹⁹ Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.
²⁰ Monash Newborn, Monash Children's Hospital, Melbourne, Victoria, Australia.
²¹ Institute of Lung Biology and Disease, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany.
²² Division of Immunology and Cell Biology, Priority Area Chronic Lung Diseases, Research Centre Borstel - Leibniz Lung Centre, Borstel, Germany.
²³ University Hospital Schleswig-Holstein Campus Kiel, Department for Internal Medicine I, Kiel, Germany.
²⁴ Translational Paediatric Pneumology, Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
²⁵ Biomedical Research in End Stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre of Lung Research (DZL), Germany.
²⁶ Institute for Asthma and Allergy Prevention, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany.
²⁷ Dr. von Hauner University Children's Hospital of Ludwig Maximilian's University, Munich, Germany.
²⁸ Department of Pneumology, LungenClinic Grosshansdorf, Grosshansdorf, Germany.
²⁹ Department of Paediatric Respiratory Medicine, Inselspital, University Children's Hospital of Bern, University of Bern, Bern, Switzerland.

PMID: 41099307
DOI: 10.1111/all.70070

Abstract

Question: Epidemiological studies suggest that respiratory viral infections are major triggers of asthma exacerbations, and clinical studies have suggested the involvement of an increased interleukin-6 (IL-6) release. What is the pathophysiological role of IL-6 in asthma exacerbation, and which mechanisms lead to enhanced IL-6 release?

Materials and methods: Exacerbations of ovalbumin-induced experimental allergic asthma were elicited in wild-type and IL-6-deficient mice by intranasal (i.n.) application of poly(I:C). Airway inflammation, cytokine expression and release, mucus production and airway hyperresponsiveness were measured. IL-6 was neutralised by i.n. anti-IL-6 antibody application. The human bronchial epithelial cell line, BEAS-2B, was stimulated with poly(I:C) and infected with human rhinovirus-16 in vitro, followed by quantification of IL6 gene expression and DNA methylation. Genome-wide DNA methylation was assessed in bronchial epithelial cells from adults with asthma (cohort I, n = 54) and in nasal epithelial cells from children and adults in the All-Age-Asthma cohort (ALLIANCE, n = 53 and n = 108 respectively).

Results: Poly(I:C)-induced experimental exacerbations in mice were preceded and paralleled by exaggerated IL-6 release in the airway epithelium, with IL-6 neutralisation completely preventing experimental exacerbations. Repetitive infection/stimulation with RV16 or poly(I:C) resulted in training of the IL-6 release in human respiratory epithelial cells. In patients, hypomethylation at the IL6 gene methylation was associated with high IL6 expression and future exacerbations.

Answer: An exaggerated IL-6 release is required for exacerbation of experimental asthma, potentially the result of viral PAMP-induced immune training of airway epithelial cells. Additionally, patients with asthma carrying the epigenetic signature of a trained IL-6 response exacerbate more frequently. These findings open new avenues to identify and treat exacerbation-prone patients.

Keywords: IL‐6; asthma; exacerbations; immune training; respiratory viruses.

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References

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Immune Training of the Interleukin 6 Gene in Airway Epithelial Cells is Central to Asthma Exacerbations

Affiliations

Immune Training of the Interleukin 6 Gene in Airway Epithelial Cells is Central to Asthma Exacerbations

Authors

Affiliations

Abstract

References

Grants and funding

LinkOut - more resources

Full Text Sources