title: Elevated expression of the NLRP3 inflammasome in neutrophilic asthma.
abstract: Asthma is a heterogeneous inflammatory airways disorder where interleukin (IL)-1β is thought to be a key mediator, especially in the neutrophilic subtype of asthma. The generation of active IL-1β requires proteolytic cleavage typically mediated through the formation of a caspase-1-containing inflammasome. This study hypothesised that an IL-1β endotype associated with the nucleotide-binding domain, leucine-rich repeat-containing family protein (NLRP)3/apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)/caspase-1 inflammasome is characteristic of patients with the neutrophilic subtype of asthma. Participants with asthma (n=85) and healthy controls (n=27) underwent clinical assessment, spirometry and sputum induction. Sputum was processed for differential cell count, gene expression and protein mediators. NLRP3 and caspase-1 expression was also determined by immunocytochemistry. Sputum macrophages were isolated (n=8) and gene expression of NLRP3 and IL-1β determined. There was significantly elevated gene expression of NLRP3, caspase-1, caspase-4, caspase-5 and IL-1β in participants with neutrophilic asthma. Protein levels of IL-1β were significantly higher in those with neutrophilic asthma and correlated with sputum IL-8 levels. Sputum macrophages, as well as sputum neutrophils in neutrophilic asthma, expressed NLRP3 and caspase-1 protein. NLRP3 inflammasome is upregulated in neutrophilic asthma and may regulate the inflammation process observed in this asthma phenotype through production of IL-1β.
authors.affiliation: Centre for Asthma and Respiratory Diseases and Hunter Medical Research Institute, Faculty of Health, School of Medicine and Public Health, The University of Newcastle, Callaghan.
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Simpson
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Baines
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Oreo
authors.forename: Lakshitha
authors.initials: L
authors.lastname: Gunawardhana
authors.forename: Peter G
authors.initials: PG
authors.lastname: Gibson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001249:Asthma / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013147:Spirometry; D013183:Sputum / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D020169:Caspases