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Lunding, L.P.* ; Weckmann, M.* ; Zissler, U.M. ; Jakwerth, C.A. ; Bodenstein-Sgró, R.* ; Webering, S.* ; Vock, C.* ; Ehlers, J.C.* ; Fernandez Ceballos, R.A.M.* ; Nemani, S.S.P.* ; Reddy, K.D.* ; Oliver, B.G.G.* ; Vermeulen, C.J.* ; van de Berge, M.* ; Ober, C.* ; Künstner, A.* ; Busch, H.* ; König, I.* ; Garbers, C.* ; Schmidt-Weber, C.B. ; Nold, M.F.* ; Yildirim, A.Ö. ; Nold-Petry, C.A.* ; Orinska, Z.* ; Bahmer, T.* ; Heyckendorf, J.* ; Hansen, G.* ; von Mutius, E. ; Rabe, K.F.* ; Dittrich, A.M.* ; Schaub, B. ; Brinkmann, F.* ; Kopp, M.V.* ; Wegmann, M.*

Immune training of the interleukin 6 gene in airway epithelial cells is central to asthma exacerbations.

Allergy, DOI: 10.1111/all.70070 (2025)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Il‐6 ; Asthma ; Exacerbations ; Immune Training ; Respiratory Viruses; Inflammatory Cytokines; Predictors

ISSN (print) / ISBN 0105-4538

e-ISSN 1398-9995

Journal Allergy

Publisher Wiley

Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa

Reviewing status Peer reviewed

Institute(s) Institute for Allergy Research (IAF)
Institute of Lung Health and Immunity (LHI)
Institute of Asthma and Allergy Prevention (IAP)

Grants Deutsches Zentrum für Lungenforschung