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

• Published in: Journal of allergy and clinical immunology Vol. 143; no. 1; pp. 305 - 315
• Main Authors: Wood, Lisa G., Li, Qian, Scott, Hayley A., Rutting, Sandra, Berthon, Bronwyn S., Gibson, Peter G., Hansbro, Philip M., Williams, Evan, Horvat, Jay, Simpson, Jodie L., Young, Paul, Oliver, Brian G., Baines, Katherine J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2019; Elsevier Limited
• Subjects: Adult; Aged; airway inflammation; Ambulatory care; Asthma; Asthma - diet therapy; Asthma - immunology; Asthma - pathology; Blood; Body mass index; Body weight loss; Carbohydrates; Cell Line; Cross-Sectional Studies; Cytokines; Dietary intake; Enzyme-linked immunosorbent assay; Fatty acids; Fatty Acids - administration & dosage; Female; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; Growth factors; Humans; IL-1β; inflammasome; Inflammasomes; Inflammasomes - immunology; Inflammation; Interleukin-1beta - immunology; Kinases; Leukocyte Count; Leukocytes (neutrophilic); Lipopolysaccharides; Male; Meals; Middle Aged; Monocytes; Neutrophils; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; Nod1 protein; Nod1 Signaling Adaptor Protein - immunology; Obesity; Obesity - diet therapy; Obesity - immunology; Obesity - pathology; Oligomerization; Palmitic acid; Peripheral blood; Polyunsaturated fatty acids; Proteins; Respiratory tract; Respiratory tract diseases; saturated fat; Sputum; Sputum - immunology; Therapeutic applications; TLR4 protein; Toll-Like Receptor 4 - immunology; Toll-like receptors; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factor-α; Australia; airway inflammation; NOD; PUFA; saturated fat; asthma; IL-1β; IL-1R; Fatty acids; SFA; NF-κB; IL-1RAP; NLR; inflammasome; NLRP3; FA; TLR; obesity; BMI
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2018.04.037

Both obesity and high dietary fat intake activate the nucleotide oligomerization domain–like receptor protein 3 (NLRP3) inflammasome. 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. 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). 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. 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. [Display omitted]