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

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

doi:10.1016/j.jaci.2021.10.003

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

J Allergy Clin Immunol. 2022 Apr;149(4):1270-1280. doi: 10.1016/j.jaci.2021.10.003. Epub 2021 Oct 19.

Authors

James W Pinkerton¹, Richard Y Kim², Alexandra C Brown³, Brittany E Rae³, Chantal Donovan², Jemma R Mayall³, Olivia R Carroll³, Md Khadem Ali⁴, Hayley A Scott³, Bronwyn S Berthon³, Katherine J Baines³, Malcolm R Starkey⁵, Nazanin Z Kermani⁶, Yi-Ke Guo⁶, Avril A B Robertson⁷, Luke A J O'Neill⁸, Ian M Adcock⁹, Matthew A Cooper¹⁰, Peter G Gibson³, Lisa G Wood³, Philip M Hansbro², Jay C Horvat¹¹

Affiliations

¹ 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.
² 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.
³ Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
⁴ 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.
⁵ 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.
⁶ Data Science Institute, Department of Computing, Imperial College London, London, United Kingdom.
⁷ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.
⁸ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
⁹ Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
¹⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
¹¹ Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia. Electronic address: Jay.horvat@newcastle.edu.au.

PMID: 34678326
DOI: 10.1016/j.jaci.2021.10.003

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.

Keywords: Asthma; IL-13; IL-5; NLRP3 inflammasomes; obesity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Asthma*
Cytokines
Humans
Inflammasomes* / metabolism
Inflammation / metabolism
Interleukin-13
Interleukin-1beta
Interleukin-5
NLR Family, Pyrin Domain-Containing 3 Protein
Obesity / complications

Substances

Cytokines
Inflammasomes
Interleukin-13
Interleukin-1beta
Interleukin-5
NLR Family, Pyrin Domain-Containing 3 Protein