Elevated expression of the NLRP3 inflammasome in neutrophilic asthma

Abstract

Asthma is a heterogeneous inflammatory airways disorder where interleukin (IL)-1b is thought to be a key mediator, especially in the neutrophilic subtype of asthma. The generation of active IL-1b requires proteolytic cleavage typically mediated through the formation of a caspase-1-containing inflammasome. This study hypothesised that an IL-1b 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 (n585) and healthy controls (n527) 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 (n58) and gene expression of NLRP3 and IL-1b determined.There was significantly elevated gene expression of NLRP3, caspase-1, caspase-4, caspase-5 and IL-1b in participants with neutrophilic asthma. Protein levels of IL-1b 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-1b. @ERSpublications The NLRP3 inflammasome may be a key regulator of neutrophilic airway inflammation in asthma through production of IL-1b

Personalised medicine in asthma: time for action

“…The third phenotype was characterised by genes of metabolic pathways, ubiquitination and mitochondrial function with paucigranulocytic inflammation and little airflow obstruction [12]. The second phenotype is in agreement with the report that in neutrophilic asthma, elevated gene expression of NLRP3, caspase-1 and IL-1β was seen in sputum macrophages [13]. This unbiased approach has thus provided an overall idea of the various pathways associated with these three phenotypes of asthma, with the clear message that each of the phenotypes is underpinned by several pathways interacting with one another.…”

The Neonatal Methylome as a Gatekeeper in the Trajectory to Childhood Asthma

“…A meta-analysis revealed that for each 10% increase in methylation at a representative CpG site in the SMAD3 DMR there is nearly a two-fold increased risk of childhood asthma [meta-analysis Odds Ratio (OR) =1.95 (95%CI: 1.23, 3.10), P=0.005]. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator that is increasingly recognized as a key asthma mediator in both children [21] and adults, especially in neutrophilic asthma [22,23].…”

“…Our data also provide clues about potentially novel mechanisms of childhood asthma inception by emphasizing the functional connection between SMAD3, a regulator of both the asthmaprotective T regulatory and the asthma-promoting Th17 cell differentiation programs [1,26], and IL-1β, a key asthma mediator in both children [21] and adults [22,23]. Indeed, in neonates who became asthmatic by age 9, SMAD3 promoter hypermethylation, an epigenetic configuration consistent with low SMAD3 expression, was strongly associated with high IL-1β production.…”

Phenotyping Asthma: Linking Clinical Features to Biomolecular Pathways

“…A high-reversibility subgroup with a post-bronchodilator FEV 1 improvement of 20% or more showed a significant improvement in ACQ score 82 . The inflammasome could underlie neutrophilic asthma and has been shown to be activated in sputum cells from patients with severe neutrophilic asthma 83,84 .…”