Saturated fatty acids, obesity, and the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in asthmatic patients.

Lisa G Wood, Qian Li, Hayley A Scott, Sandra Rutting, Bronwyn S Berthon, Peter G Gibson, Philip M Hansbro, Evan Williams, Jay Horvat, Jodie L Simpson, Paul Young, Brian G Oliver, Katherine J Baines

Journal: The Journal of allergy and clinical immunology 2019;143(1):305-315

PMID: 29857009

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

Both obesity and high dietary fat intake activate the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome.

OBJECTIVE

We aimed to examine NLRP3 inflammasome activity in the airways of obese asthmatic patients after macronutrient overload and in immune cells challenged by inflammasome triggers.

METHODS

Study 1 was a cross-sectional observational study of nonobese (n = 51) and obese (n = 76) asthmatic adults. Study 2 was a randomized, crossover, acute feeding study in 23 asthmatic adults (n = 12 nonobese and n = 11 obese subjects). Subjects consumed 3 isocaloric meals on 3 separate occasions (ie, saturated fatty acid, n-6 polyunsaturated fatty acid, and carbohydrate) and were assessed at 0 and 4 hours. For Studies 1 and 2, airway inflammation was measured based on sputum differential cell counts, IL-1β protein levels (ELISA), and sputum cell gene expression (Nanostring nCounter). In Study 3 peripheral blood neutrophils and monocytes were isolated by using Ficoll density gradient and magnetic bead separation and incubated with or without palmitic acid, LPS, or TNF-α for 24 hours, and IL-1β release was measured (ELISA).

RESULTS

In Study 1 NLRP3 and nucleotide oligomerization domain 1 (NOD1) gene expression was upregulated, and sputum IL-1β protein levels were greater in obese versus nonobese asthmatic patients. In Study 2 the saturated fatty acid meal led to increases in sputum neutrophil percentages and sputum cell gene expression of Toll-like receptor 4 (TLR4) and NLRP3 at 4 hours in nonobese asthmatic patients. In Study 3 neutrophils and monocytes released IL-1β when challenged with a combination of palmitic acid and LPS or TNF-α.

CONCLUSION

The NLRP3 inflammasome is a potential therapeutic target in asthmatic patients. Behavioral interventions that reduce fatty acid exposure, such as weight loss and dietary saturated fat restriction, warrant further exploration.

Address: Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia. Electronic address: [email protected].; Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia.; Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia; Woolcock Institute of Medical Research, Sydney, Australia.; Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia; Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, Australia.; Woolcock Institute of Medical Research, Sydney, Australia.

DOI: 10.1016/j.jaci.2018.04.037

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MeSH Terms: Adult, Aged, Female, Humans, Male, Middle Aged, Asthma, Cell Line, Cross-Sectional Studies, Fatty Acids, Gene Expression Regulation, Inflammasomes, Interleukin-1beta, Leukocyte Count, NLR Family, Pyrin Domain-Containing 3 Protein, Nod1 Signaling Adaptor Protein, Obesity, Sputum, Toll-Like Receptor 4, Tumor Necrosis Factor-alpha