Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma.

Abstract Background Obesity is a risk factor for asthma and obese asthmatics are more likely to have severe, steroid-insensitive 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. Objective To investigate how obesity affects the pathogenesis and severity of asthma and identify effective therapies for obesity-associated disease. Methods We assessed associations between body mass index 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 Body mass index and inflammasome responses positively correlate with increased IL-5 and IL-13 expression, 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 in experimental asthma. Inhibition of NLRP3 inflammasome responses reduces steroid-insensitive airway hyper-responsiveness but has no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduces obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyper-responsiveness in experimental asthma. 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.