IL‐1 signaling pathway molecules as key markers in childhood asthma

Abstract

Objective The prevalence of childhood asthma has been increasing in recent years. This study aims to investigate the involvement of the key molecules of IL‐1 (interleukin‐1) signaling pathways in pediatric patients with asthma. Methods Differentially expressed genes (DEGs) associated with IL‐1 signaling pathways were identified with RNA‐seq from peripheral blood samples collected from asthmatic or healthy children and were further verified in clinical peripheral blood samples. Cellular models and asthmatic mice were subsequently developed to validate the identified asthmatic markers. Results Among the DEGs identified by RNA‐seq, eight signal transducers associated with the IL‐1 signaling network, namely IL‐1RN, IL‐1β, IL‐1RAP, IRAK3, IL‐1R1, MYD88, IRAK2, and PELI1, were found to be substantially upregulated in children with asthma. Interestingly, a significant serially increased expression of four genes (IL‐1RN, IL‐1RAP, IRAK3, and PELI1) was observed in healthy subjects, patients with chronic persistent asthma and patients with acute exacerbation asthma. In particular, these four genes were continuously overexpressed in recurrent patients. A significant induction of the above four genes was then observed in house dust mite (HDM)–stimulated peripheral blood mononuclear cells (PBMCs) and ovalbumin (OVA)–induced asthmatic mice. In addition, a time‐dependent induction of IL‐1RAP and PELI1 was also detected in HDM‐treated THP‐1 cells, an acute monocytic leukemia cell line. Conclusions These results demonstrate that IL‐1RN, IL‐1RAP, IRAK3, and PELI1, which are signal transducers of the IL‐1 signaling pathway, could serve as biomarkers for the pathogenesis of childhood asthma and for potential therapeutic targets of asthma.

Innate immune responses are increased in children with acute asthma exacerbation

“…As a caspase‐regulated process, pyroptosis mediates airway epithelial cell death 41 and pro‐inflammatory responses in lung macrophages 42 . Recently Wei et al 43 . observed increased expression levels of genes involved in IL‐1 signaling pathway (IL‐1RN, IL‐1RAP, IRAK3, and PELI1) in children with persistent asthma and those with acute asthma exacerbation.…”

“…40 As a caspase-regulated process, pyroptosis mediates airway epithelial cell death 41 and pro-inflammatory responses in lung macrophages. 42 Recently Wei et al 43 observed increased expression levels of genes involved in IL-1 signaling pathway (IL-1RN, IL-1RAP, IRAK3, and PELI1) in children with persistent asthma and those with acute asthma exacerbation. Despite evidence for IL-1 signaling in our gene expression data, we observed a lack of IL-1α and IL-1β protein levels in plasma which may be attributed to increased IL-1RA protein levels.…”

IL1RAP expression and the enrichment of IL‐33 activation signatures in severe neutrophilic asthma

“…IL1RAP mRNA is increased in PBMCs from children with asthma compared with healthy controls, and its expression is enhanced with increasing asthma severity and during exacerbations. 44 Selective blocking of IL1RAP with a monoclonal antibody (mAB‐mR3) inhibits signalling not only by IL‐33 but also IL‐1 and IL‐36 pathways. 45 In an ovalbumin‐driven murine model of asthma, MAB‐mR3 reduced lung neutrophilia as well as suppressing eosinophilia.…”

Mast cell chymase regulates extracellular matrix remodeling-related events in primary human small airway epithelial cells

“…However, chymase also induced release of the anti-inflammatory factor IL-1RA. Considering that IL-1 signaling has been implicated in asthma, 35,36 IL-1RA induction by chymase could have a regulatory role by downregulating the effects of IL-1 under such circumstances. Hence, chymase induces both proinflammatory and antiinflammatory compounds in HSAECs, and whether the effects of chymase on the airway epithelial cells result in an altogether proinflammatory or anti-inflammatory outcome is thus not certain.…”