Question: Epidemiological studies suggest 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? Material & Methods: Exacerbations of ovalbumin-induced experimental allergic asthma were elicited in wildtype and IL-6 deficient mice by intra-nasal (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. Human bronchial epithelial cells were exposed to poly(I:C) or infected with human rhinovirus-16, with IL6 expression and DNA methylation quantified. Genome-wide DNA methylation was assessed in airway 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.