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

• Published in: Journal of allergy and clinical immunology 2022-04, Vol.149 (4), p.1270-1280
• Main Authors: Pinkerton, James W., Kim, Richard Y., Brown, Alexandra C., Rae, Brittany E., Donovan, Chantal, Mayall, Jemma R., Carroll, Olivia R., Khadem Ali, Md, Scott, Hayley A., Berthon, Bronwyn S., Baines, Katherine J., Starkey, Malcolm R., Kermani, Nazanin Z., Guo, Yi-Ke, Robertson, Avril A.B., O’Neill, Luke A.J., Adcock, Ian M., Cooper, Matthew A., Gibson, Peter G., Wood, Lisa G., Hansbro, Philip M., Horvat, Jay C.
• Format: Article
• Language: English
• Subjects: Asthma; Cytokines; Humans; IL-13; IL-5; Inflammasomes - metabolism; Inflammation - metabolism; Interleukin-13; Interleukin-1beta; Interleukin-5; NLR Family, Pyrin Domain-Containing 3 Protein; NLRP3 inflammasomes; obesity; Obesity - complications
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2021.10.003

Obesity is a risk factor for asthma, and obese asthmatic individuals 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. We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease. We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain–containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet–induced obesity and asthma. Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet–induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet–induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma. We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine–targeted biologics and inflammasome inhibitors.