Translational and clinical immunology
Saturated fatty acids, obesity, and the nucleotide oligomerization domain–like receptor protein 3 (NLRP3) inflammasome in asthmatic patients

https://doi.org/10.1016/j.jaci.2018.04.037Get rights and content

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.

Section snippets

Study 1: Obese versus nonobese asthmatic patients—Cross-sectional comparison of inflammatory pathways

A cross-sectional observational study was conducted in 127 adult asthmatic patients categorized as nonobese (body mass index [BMI], <30 kg/m2; n = 51) or obese (BMI, ≥30 kg/m2; n = 76). Data from a subset of these subjects have been reported previously.14, 15, 16 Subjects fasted overnight, and asthma medications were withheld (short-acting bronchodilators, 6 hours; long-acting bronchodilators and inhaled corticosteroids, 24 hours). Blood was collected, and spirometry and sputum induction were

Obese versus nonobese asthmatic patients: Cross-sectional comparison of inflammatory pathways

Subjects' characteristics are described in Table II. Obese asthmatic patients had higher plasma levels of total FAs, SFAs, monounsaturated FAs, C16:0, C18:0, and C20:4n-6 compared with nonobese asthmatic patients. Nanostring analysis of sputum cell gene expression in obese versus nonobese asthmatic patients identified 13 genes with a fold change of greater than 1.5 that were expressed differentially (Table III). The most significantly upregulated gene in obese asthmatic patients was IL5,

Discussion

This study provides important new insight into airway NLRP3 inflammasome activity in asthmatic patients with a high BMI and after excess macronutrient intake. We have shown increased circulating FA levels, activation of the innate immune receptor NOD1, and increased NLRP3 activity and IL-1β protein levels in obese asthmatic patients. We have also determined that SFAs induce postprandial airway inflammation with increased TLR4, NLRP3, and IL-1 pathway gene expression in nonobese

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    The project was funded by the National Health and Medical Research Council (NHMRC) of Australia. P.G.G. is supported by an NHMRC Practitioner Fellowship, and P.M.H. is supported by an NHMRC Principal Research Fellowship and a Brawn Fellowship, Faculty of Health and Medicine, University of Newcastle.

    Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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