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. 2024 Jun 20;63(6):2400005.
doi: 10.1183/13993003.00005-2024. Print 2024 Jun.

IL-33 induced gene expression in activated Th2 effector cells is dependent on IL-1RL1 haplotype and asthma status

Akshaya Keerthi Saikumar Jayalatha  1   2 , Marlies E Ketelaar  1   3   2 , Laura Hesse  1   2 , Yusef E Badi  4 , Nazanin Zounemat-Kermani  4 , Sharon Brouwer  1 , Nicole F Dijk  3 , Maarten van den Berge  5 , Victor Guryev  6 , Ian Sayers  7 , Judith E Vonk  8 , Ian M Adcock  4 , Gerard H Koppelman  3 , Martijn C Nawijn  9
Affiliations

IL-33 induced gene expression in activated Th2 effector cells is dependent on IL-1RL1 haplotype and asthma status

Akshaya Keerthi Saikumar Jayalatha et al. Eur Respir J. .

Abstract

IL-33 response in Th2 cells is specific to asthma and represents a high risk haplotype, highlighting its role in airway wall cells. Yet, its detection is challenging in bulk asthma transcriptomes due to the scarcity of effector Th2 cells. https://bit.ly/3WhuMbo

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Conflict of interest statement

Conflict of interest: All author report that funding for this manuscript was provided by GlaxoSmithKline (GSK) and Lung Foundation Netherlands (3.2.09.081JU). M.C. Nawijn reports support for the present manuscript from the Netherlands Ministry of Economic Affairs and Climate Policy by means of the PPP allowance. M.E. Ketelaar reports an unpaid leadership position as young investigator board member of the Netherlands Respiratory Society, outside the submitted work. L. Hesse reports payment for expert testimony from Chiesi, outside the submitted work. M. van den Berge reports grants from Chiesi, AstraZeneca, Novartis, Genentech and Roche, outside the submitted work. I. Sayers reports grants from Boehringer Ingelheim and the Biotechnology and Biological Sciences Research Council (BBSRC), outside the submitted work. I.M. Adcock reports support for the present manuscript from EU-IMI; and outside the submitted work, reports grants from GSK, MRC and EPSRC, consulting fees from GSK, Sanofi, Chiesi and Kinaset, lecture honoraria from AstraZeneca, Sanofi, Eurodrug and Sunovion, payment for expert testimony from Chiesi and travel support from AstraZeneca. G.H. Koppelman reports grants from Lung Foundation Netherlands, Teva the Netherlands, European Union H2020 programme, Ubbo Emmius Foundation and Vertex, consulting fees from AstraZeneca and Pure IMS, and lecture honoraria from Sanofi Genzyme; outside the submitted work. The remaining authors have no potential conflicts of interest to disclose.

Figures

FIGURE 1
FIGURE 1
a) Study design: asthma-associated single nucleotide polymorphisms (SNPs) in the IL-1RL1 gene (rs1420101 and rs4988956) with the selected risk and protective alleles. CD4+CD25− T cells from asthma patients and healthy individuals with different IL-1RL1 haplotypes were isolated and differentiated into Th2 cells followed by CD3/CD28 activation with or without exogenous interleukin (IL)-33. RNA sequencing of Th2 cells was used to generate a gene signature, which was then validated in various datasets (CD4+, Human Lung Cell Atlas (HLCA), INDURIAN, U-BIOPRED) for clinical asthma phenotype associations. b) Clinical characteristics of the peripheral blood mononuclear cell donors selected from NORM (controls) and ROORDA (asthma patients) cohorts. Data are presented as mean±sd or median (interquartile range), unless otherwise indicated. c and d) Volcano plots showing gene expression changes in Th2 cells (n=29), after CD3/CD28 activation (c) and by the additional presence of IL-33 (d), with 12 038 genes tested. Significant gene upregulation (brown dots) and downregulation (orange dots) are highlighted. False discovery rate-adjusted p-value threshold is 0.05. e–h) Volcano plots for differentially expressed genes induced by IL-33 in high risk (n=14; e) and low risk haplotype carriers (n=15; f), or in asthma patients (n=15; g), and healthy controls (n=14; h). i–k) Enrichment of the Th2 IL33 gene signature in the HLCA [7], in CD4+ T cells isolated from bronchial biopsies of patients with asthma and healthy controls [8], and in bronchial biopsies from patients with asthma and healthy controls from the INDURAIN cohort [9]. l and m) Enrichment scores for the IL-33 gene signature in U-BIOPRED sputum transcriptomic data, analysed across different disease groups, asthma phenotypes, and transcriptome-associated clusters (TAC) groups generated through unsupervised clustering of transcriptome data [10]. DC: dendritic cell; NK: natural killer; GSVA: gene set variation analysis; MMA: mild/moderate asthma patients; SA: severe asthma patients. Statistical tests include t-test and Wilcoxon rank-sum test.
FIGURE 1
FIGURE 1
Continued.
See this image and copyright information in PMC

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