Diet-Induced Obesity Worsens Allergen-Induced Type 2/Type 17 Inflammation in Airways by Enhancing DUOX1 Activation

More than 50% of people with asthma in the US are obese, and obesity often worsens allergic asthma symptoms and impairs treatment response. Based on previously established roles of the epithelial NADPH oxidase DUOX1 in allergic airway inflammation, the study addressed the potential involvement of DUOX1 in altered allergic inflammation in the context of obesity. Intranasal house dust mite (HDM) allergen challenge of subjects with allergic asthma induced rapid secretion of IL-33, then IL-13, into the nasal lumen. These responses were significantly enhanced in obese asthmatic subjects (BMI >30). Induction of diet-induced obesity (DIO) in mice by high-fat diet (HFD) feeding similarly enhanced acute airway responses to intranasal HDM challenge, particularly concerning secretion of IL-33 and typed 2/type 3 cytokines, and this was associated with enhanced epithelial DUOX1 expression and was avoided in DUOX1-deficient mice. DIO also enhanced DUOX1-dependent features of chronic HDM-induced allergic inflammation. DIO was associated with enhanced adipokine leptin in the airways, and leptin enhanced DUOX1-dependent IL-13 and mucin production in airway epithelial cells. In conclusion, augmented inflammatory airway responses to HDM in obesity are attributed to increased airway epithelial DUOX1 and increased airway epithelial leptin signaling.