IL1RAP expression and the enrichment of IL‐33 activation signatures in severe neutrophilic asthma. Issue 1 (28th August 2022) - Badi, Yusef Eamon
Abstract: Background: Interleukin (IL)‐33 is an upstream regulator of type 2 (T2) eosinophilic inflammation and has been proposed as a key driver of some asthma phenotypes. Objective: To derive gene signatures from in vitro studies of IL‐33‐stimulated cells and use these to determine IL‐33‐associated enrichment patterns in asthma. Methods: Signatures downstream of IL‐33 stimulation were derived from our in vitro study of human mast cells and from public datasets of in vitro stimulated human basophils, type 2 innate lymphoid cells (ILC2), regulatory T cells (Treg) and endothelial cells. Gene Set Variation Analysis (GSVA) was used to probe U‐BIOPRED and ADEPT sputum transcriptomics to determine enrichment scores (ES) for each signature according to asthma severity, sputum granulocyte status and previously defined molecular phenotypes. Results: IL‐33‐activated gene signatures were cell‐specific with little gene overlap. Individual signatures, however, were associated with similar signalling pathways (TNF, NF‐κB, IL‐17 and JAK/STAT signalling) and immune cell differentiation pathways (Th17, Th1 and Th2 differentiation). ES for IL‐33‐activated gene signatures were significantly enriched in asthmatic sputum, particularly in patients with neutrophilic and mixed granulocytic phenotypes. IL‐33 mRNA expression was not elevated in asthma whereas the expression of mRNA for IL1RL1, the IL‐33 receptor, was up‐regulated in the sputum of severe eosinophilic asthma. The mRNA expression for IL1RAP, the IL1RL1 co‐receptor, was greatest in severe neutrophilic and mixed granulocytic asthma. Conclusions: IL‐33‐activated gene signatures are elevated in neutrophilic and mixed granulocytic asthma corresponding with IL1RAP co‐receptor expression. This suggests incorporating T2‐low asthma in anti‐IL‐33 trials. Abstract : Stimulation of human mast cells, basophils, ILC2 cells and HUVECs with IL‐33 generates distinct gene expression patterns but similar pathways are activated. We produced IL‐33‐activated gene signatures and used GSVA and showed enrichment of these signatures in patients with neutrophilic and mixed granulocytic asthma. These patients had the highest expression of the IL‐33 receptor co‐receptor IL1RAP.Abbreviations: BAS, basophil; HUVECs, human umbilical vein endothelial cells; IL, interleukin; ILC2, type 2 innate lymphoid cell; IL1RAP, IL‐1 receptor accessory protein; JAK, Janus kinase; MC, mast cell; STAT, signal transducer and activator of transcription; Th, T helper; TNF, tumor necrosis factor