IL-33 induced gene expression in activated Th2 effector cells is dependent on IL-1RL1 haplotype and asthma status
Authors: Akshaya Keerthi Saikumar Jayalatha, Marlies E. Ketelaar, Laura Hesse, Yusef E. Badi, Nazanin Zounemat-Kermani, Sharon Brouwer, Nicole F. Dijk, Maarten van den Berge, Victor Guryev, Ian Sayers, Judith E. Vonk, Ian M. Adcock, Gerard H. Koppelman, Martijn C. Nawijn
Journal: European Respiratory Journal (2024)

Asthma is a heterogeneous respiratory disease caused by the interaction between environmental and genetic factors [1]. The IL-33 and IL-1RL1 genes are strongly associated with childhood-onset and type-2 high asthma, and the asthma risk alleles amplify IL-33 pathway activity [2]. Environmental factors such as allergens and viral infections trigger bronchial epithelial cells to release IL-33, which can activate signalling by binding to the IL-1RL1/IL-1RAcP receptor complex [3], and contribute to hyper-responsiveness, remodelling, and chronic type 2 inflammation of the airways [4]. IL-1RL1 is expressed in immune and structural cells of the airways, such as epithelial cells, mast cells, macrophages, Th2 cells, and ILC2 s. IL-1RL1 encodes two protein isoforms: the transmembrane receptor subunit (IL-1RL1b) and a soluble (IL-1RL1a) isoform that functions as an antagonistic decoy receptor. Human Th2 cells respond to IL-33 by enhancing cytokine production [5]. Genetic variation at the IL-1RL1 locus, particularly rs1420101 in intron 5 and a block of 4 non-synonymous SNPs in full LID in exon 11, alter IL-1RL1 expression levels and IL-33 induced signalling activity [2, 6]. However, it is not known whether genetic variation at the IL-1RL1 locus affects the response of Th2 cells to IL-33. Therefore, we tested whether IL-1RL1 haplotype altered the IL-33 induced response of Th2 cells from healthy controls and patients with asthma. Moreover, we explored whether IL-33-induced gene signatures from Th2 cells could identify subgroups of asthma patients in transcriptomic datasets. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of Interest: Funding for this manuscript was provided by GlaxoSmithKline (GSK) and Lung Foundation Netherlands [3.2.09.081JU]. Conflict of Interest: Martijn C Nawijn reports support for the present manuscript from The Netherlands Ministry of Economic Affairs and Climate Policy by means of the PPP-allowance. Conflict of Interest: Maria Elizabeth Ketelaar reports an unpaid leadership position as Board member Young Investigator Board of Netherlands Respiratory Society, outside the submitted work. Conflict of Interest: Laura Hesse reports payment for expert testimony from Chiesi; outside the submitted work. Conflict of Interest: Maarten van den Berge reports grants from Chiesi, Astra Zeneca, Novartis, Genentech, Roche; outside the submitted work. Conflict of Interest: Ian Sayers reports grants from Boehringer Ingelheim, Biotechnology and Biological Sciences Research Council (BBSRC); outside the submitted work. Conflict of Interest: Ian M Adcock reports support for the present manuscript from EU-IMI. Outside the submitted work, Ian M Adcock reports grants from GSK, MRC, EPSRC; consulting fees from GSK, Sanofi, Chiesi, Kinaset; lecture honoraria from AstraZeneca, Sanofi, Eurodrug, Sunovion; payment for expert testimony from Chiesi; travel support from AstraZeneca. Conflict of Interest: Gerard H. Koppelman reports grants from Lung Foundation Netherlands, Teva the Netherlands, European Union H2020 program, Ubbo Emmius Foundation, Vertex; consulting fees from AstraZeneca, Pure IMS; lecture honoraria from Sanofi Genzyme; outside the submitted work. Conflict of Interest: All other authors have nothing to disclose.