Lisa G Wood1, Qian Li2, Hayley A Scott2, Sandra Rutting3, Bronwyn S Berthon2, Peter G Gibson4, Philip M Hansbro2, Evan Williams2, Jay Horvat2, Jodie L Simpson2, Paul Young5, Brian G Oliver5, Katherine J Baines2. 1. Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia. Electronic address: lisa.wood@newcastle.edu.au. 2. Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia. 3. Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia; Woolcock Institute of Medical Research, Sydney, Australia. 4. Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia; Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, Australia. 5. Woolcock Institute of Medical Research, Sydney, Australia.
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 andn = 11 obese subjects). Subjects consumed 3 isocaloric meals on 3 separate occasions (ie, saturated fatty acid, n-6polyunsaturated 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.
RCT Entities:
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 asthmaticpatients 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 asthmaticpatients. 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.
Authors: Anne M Fitzpatrick; Abby D Mutic; Ahmad F Mohammad; Susan T Stephenson; Jocelyn R Grunwell Journal: J Allergy Clin Immunol Pract Date: 2021-10-22
Authors: J A Tuazon; B Kilburg-Basnyat; L M Oldfield; R Wiscovitch-Russo; K Dunigan-Russell; A V Fedulov; K J Oestreich; K M Gowdy Journal: Curr Allergy Asthma Rep Date: 2022-04-08 Impact factor: 4.919