METABOLIC ALTERATIONS IN AIRWAY EPITHELIUM IN ALLERGIC ASTHMA

Allergic asthma is a chronic inflammatory disease of the lung. It is thought to arise as a result of aberrant type-2 immune responses to environmental allergens in susceptible individuals. Among the allergens, sensitization to house dust mite (HDM) is one of the major risk factors for the onset of asthma. However, the mechanisms driving the initiation of such inappropriate type-2 immune responses following allergen exposure remain unclear. Recent studies have shown that the release of the cytokine interleukin 33 (IL-33) from airway epithelial cells following allergen recognition by pattern recognition receptors (PRRs) expressed on these cells dictates the nature and magnitude of the immune responses. However, the allergen-induced signals regulating the release of IL-33 remain to be fully established. Based on recent evidence that asthma is associated with increased glycolysis activity in the lungs, we hypothesized that HDM exposure induces increased glycolysis in airway epithelial cells, facilitating the secretion of IL-33 and allergic airway responses. We report for the first time that HDM induces immediate increases in glycolytic flux in airway epithelial cells that is associated with the early release of IL-33. Mechanistically, we confirm that HDM-induced IL-33 release is mediated by cytoskeletal rearrangement, which results in rapid deprivation of intracellular ATP. Such energy deprivation leads to activation of the homeostasis regulator AMP-activated protein kinase (AMPK), resulting in increased glycolysis and production of glycolytic ATP that in turn, facilitates the translocation of IL-33 to the extracellular milieu. Further analyses reveal that blockade of glycolysis in vivo abrogates HDM-induced allergic airway responses likely via inhibition of IL-33 release, which in turns inhibits type-2 cytokine IL-13 production from its potent early innate source, type-2 innate lymphoid cells (ILC2s). Collectively, these results suggest that allergic asthma may arise due to allergen-driven changes in airway epithelial cell metabolism that facilitates early, immediate release of IL-33 and the initiation of type-2 inflammation through recruitment and activation of ILC2s. Prevention of allergen-driven metabolic changes in the airway epithelium may provide a means to mitigate the initiation of type-2 immune response-mediated inflammation and the onset of asthma, offering a promising new therapeutic avenue for combating this disease