Allergy - 2022 - Badi - IL1RAP expression and the enrichment of IL‐33 activation signatures in severe neutrophilic asthma.pdf (5.9 MB)
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IL1RAP expression and the enrichment of IL-33 activation signatures in severe neutrophilic asthma.

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posted on 16.09.2022, 10:17 authored by Yusef Eamon Badi, Barbora Salcman, Adam Taylor, Batika Rana, Nazanin Zounemat Kermani, John H Riley, Sally Worsley, Sharon Mumby, Sven-Eric Dahlen, David Cousins, Silvia Bulfone-Paus, Karen Affleck, Kian Fan Chung, Stewart Bates, Ian M Adcock

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.

Funding

Biotechnology and Biological Sciences Research Council. Grant Number: BIDS3000032503

Imperial College Jameel Trust

MRC-GSK Alliance: Mechanisms of interplay between allergy and viruses in asthma

Medical Research Council

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National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) Leicester

United Kingdom Refractory Asthma Stratification Programme (RASP-UK)

Medical Research Council

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MICA: Korea-UK PRISM consortium: Establishing Precision Medicine in severe asthma

Medical Research Council

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MRC-Asthma UK Centre in Allergic Mechanisms of Asthma

Medical Research Council

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National Institute for Health Research (NIHR) BRC at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London

Asthma UK. Grant Number: 09/020

Imperial College London

Flow cytometric isolation and characterisation of cells from human lung samples

Wellcome Trust

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Health assessment across biological length scales for personal pollution exposure and its mitigation (INHALE)

Engineering and Physical Sciences Research Council

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'COVAIR': Is SARS-CoV-2 airborne and does it interact with particle pollutants?

Engineering and Physical Sciences Research Council

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Innovative Medicines Initiative (IMI). Grant Numbers: No.831434, No.853850, No.115010

History

Author affiliation

Department of Respiratory Sciences, University of Leicester

Version

VoR (Version of Record)

Published in

Allergy

Publisher

Wiley

issn

0105-4538

eissn

1398-9995

Copyright date

2022

Available date

16/09/2022

Spatial coverage

Denmark

Language

eng

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