Interaction between type 2 cytokine and inflammasome responses in the pathogenesis of obesity-associated asthma

Background: Obesity is a risk factor for asthma and obese asthmatics are more likely to have severe disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type-2 immunity and eosinophilic inflammation have been described but the links remain unknown. Methods: We assessed correlations between BMI and inflammasome responses with type-2 immune responses in the sputum of 25 subjects with asthma. Functional roles for NLRP3 inflammasome and type-2 cytokine responses in driving key features of disease were examined in experimental high fat diet-induced obesity and asthma. Results: BMI and inflammasome responses positively correlate with increased IL-5 and IL-13 expression, eosinophil numbers, and C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High fat diet-induced obesity results in steroid-insensitive airway hyper-responsiveness in both the presence and absence of experimental asthma. High fat diet-induced obesity is also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not the lumen. Inhibition of NLRP3 inflammasome responses reduces steroid-insensitive airway hyper-responsiveness but has no effect on IL-5 or IL-13 responses. Depletion of IL-5 and IL-13 reduces obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyper-responsiveness. Conclusion: We show a relationship between type-2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of type-2 cytokine-targeted biologics and inflammasome inhibitors.