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

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.

• Lunding, L. P.
• Weckmann, M.
• Zissler, U. M.
• Jakwerth, C.
• 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, AÖ
• 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.