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

Malcolm R Starkey, Jay C Horvat, Philip M Hansbro, Lisa G Wood, Peter G Gibson, Matthew A Cooper, Ian M Adcock, Luke A J O'Neill, Avril A B Robertson, Yi-Ke Guo, Nazanin Z Kermani, James W Pinkerton, Katherine J Baines, Bronwyn S Berthon, Hayley A Scott, Md Khadem Ali, Olivia R Carroll, Jemma R Mayall, Chantal Donovan, Brittany E Rae, Alexandra C Brown, Richard Y Kim

Journal: The Journal of allergy and clinical immunology 2022;149(4):1270-1280

PMID: 34678326

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

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.

OBJECTIVE

We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

Address: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia; Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia; Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, Calif.; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia; Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Australia; Priority Research Centre GrowUpWell, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.; Data Science Institute, Department of Computing, Imperial College London, London, United Kingdom.; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.; Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.; Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia. Electronic address: [email protected].

DOI: 10.1016/j.jaci.2021.10.003

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MeSH Terms: Asthma, Cytokines, Humans, Inflammasomes, Inflammation, Interleukin-13, Interleukin-1beta, Interleukin-5, NLR Family, Pyrin Domain-Containing 3 Protein, Obesity