Exposure to Allergens and Proinflammatory Mediators Modulate Airway Epithelial Cell Innate Responses, Metabolism, and Physiology

Abstract

Lungs and airways health and protection depend on the integrity of airway epithelium. Insulin is a growth hormone that through activation of several signaling pathways play a central role to maintain cellular growth and activate metabolism. Airway epithelium is in constant exposure to inhaled agents like pathogens, allergens, pollutants, and particular matters. Airborne allergens like cockroach or house dust mite (HDM) contain proteases that can interact with airway epithelium and initiate immune responses through activation of airway epithelial cells and innate immune cells. Airway epithelium cytokines and innate immune cells promote activation of adaptive immune cells like Th2 lymphocytes that produce proinflammatory mediators like interleukin-4 (IL-4), IL-13, and IL-5. T helper 2 (Th2) cytokines amplify the immune responses and stimulate airway epithelial cells to release CCL chemotactic factors/eotaxins that attract eosinophils to the site of inflammation. Airway epithelium exposure to inhaled irritants and excessive inflammatory responses is known to disrupt epithelium integrity and exacerbate inflammatory responses. Th2 inflammation in asthma is associated with epithelial injury, epithelial remodeling, and metabolic alterations. Increased expression of inflammatory mediators tumor necrosis factor (TNF) and IL-6 in metabolically active tissues have been associated with cellular damage and insulin resistance. Inducible AECs local inflammation was shown to trigger systemic inflammation, insulin resistance, and impaired glucose metabolism, and the severity of inflammation correlated with impaired glucose metabolism. Several studies showed that insulin resistance increased the risk of aeroallergen sensitization and developing asthma-like symptoms. In this project we hypothesized that exposure of airway epithelial cells (AECs) to allergens and proinflammatory mediators may modulate Th2 immune cell responses, induce insulin resistance and metabolic shifts. First, we examined the effect of cockroach and house dust mite on IL-13 and IL-4-induced inflammatory responses. AECs were cultured and stimulated with cockroach or house dust mite, IL-13, IL-4, or a combination of an allergen and IL-13 or IL-4. IL-13 and IL-4 induced effects were measured. Then, we tested the effect of cockroach, house dust mite, TNF or IL-6-induced inflammatory responses on physiological epithelial changes and insulin-induced effects. Epithelial proliferation, resistance, energetic phenotype changes, and insulin induced activation of PI3K/Akt were examined. We showed that serine proteases of cockroach extract prevented IL-13-induced expression of eosinophil chemokine CCL26 from AECs. Depletion of CCL26 was previously shown to delay resolution of airway allergic inflammation which may result in prolonged eosinophilia. Prolonged inflammation was linked to altered metabolism and insulin action in several studies. We showed for the first time that house duct mite and TNF modulated insulin effects in AECs. TNF and HDM changed insulin-induced ATP production in AECs. Additionally, TNF reduced insulin-induced Akt phosphorylation, reduced epithelial barrier function and recovery after injury. Our data suggest that cockroach serine proteases and TNF may interfere with the Th2-mediated proinflammatory effects, regulate AECs energetic phenotype, and induce insulin resistance. These inflammatory and metabolic changes exacerbate the pathogenesis of asthma which may alter immune cell responses.