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. 2025 Feb;155(2):491-504.e9.
doi: 10.1016/j.jaci.2024.10.027. Epub 2024 Nov 7.

IL-9 sensitizes human TH2 cells to proinflammatory IL-18 signals in atopic dermatitis

Stefanie Schärli  1 , Fabian Luther  1 , Jeremy Di Domizio  2 , Christina Hillig  3 , Susanne Radonjic-Hoesli  1 , Kathrin Thormann  1 , Dagmar Simon  1 , Amalie Thorsti Møller Rønnstad  4 , Iben Frier Ruge  4 , Blaine G Fritz  5 , Thomas Bjarnsholt  6 , Angela Vallone  1 , Sanja Kezic  7 , Michael P Menden  8 , Lennart M Roesner  9 , Thomas Werfel  9 , Jacob P Thyssen  4 , Stefanie Eyerich  10 , Michel Gilliet  2 , Nicole L Bertschi  1 , Christoph Schlapbach  11
Affiliations
Free article

IL-9 sensitizes human TH2 cells to proinflammatory IL-18 signals in atopic dermatitis

Stefanie Schärli et al. J Allergy Clin Immunol. 2025 Feb.
Free article

Abstract

Background: TH2 cells crucially contribute to the pathogenesis of atopic dermatitis (AD) by secreting high levels of IL-13 and IL-22. Yet the upstream regulators that activate TH2 cells in AD skin remain unclear. IL-18 is a putative upstream regulator of TH2 cells because it is implicated in AD pathogenesis and has the capacity to activate T cells.

Objective: We sought to decipher the role of IL-18 in TH2 responses in blood and skin of AD patients.

Methods: Peripheral blood mononuclear cells and skin biopsy samples from AD patients and healthy donors were used. Functional assays were performed ex vivo using stimulation or blocking experiments. Analysis was performed by flow cytometry, bead-based multiplex assays, RT-qPCR, RNA-Seq, Western blot, and spatial sequencing.

Results: IL-18Rα+ TH2 cells were enriched in blood and lesional skin of AD patients. Of all the cytokines for which TH2 cells express the receptor, only IL-9 was able to induce IL-18R via an IL-9R-JAK1/JAK3-STAT1 signaling pathway. Functionally, stimulation of circulating TH2 cells with IL-18 induced secretion of IL-13 and IL-22, an effect that was enhanced by costimulation with IL-9. Mechanistically, IL-18 induced TH2 cytokines via activation of IRAK4, NF-κB, and AP-1 signaling in TH2 cells, and neutralization of IL-18 inhibited these cytokines in cultured explants of AD skin lesions. Finally, IL-18 protein levels correlated positively with disease severity in lesional AD skin.

Conclusion: Our data identify a novel IL-9/IL-18 axis that contributes to TH2 responses in AD. Our findings suggest that both IL-9 and IL-18 could represent upstream targets for future treatment of AD.

Keywords: Atopic dermatitis (AD); IL-9 receptor (IL-9R); interleukin-1 receptor–associated kinase 4 (IRAK4); interleukin-18 (IL-18); interleukin-18 receptor (IL-18R); interleukin-9 (IL-9); pathogenic T(H)2 cells (pT(H)2); upstream regulator of T(H)2 cells.

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Conflict of interest statement

Disclosure statement Supported by the Swiss National Science Foundation (grant 320030_192479), Bern Center for Precision Medicine (pilot project grant), Ruth & Arthur Scherbarth Foundation (project grant) (all to C.Sc.), the SKINTEGRITY.CH collaborative research project (S.S., F.L., J.D.D., M.G., N.L.B., and C.Sc.), the Deutsche Forschungsgemeinschaft through TUM International Graduate School of Science and Engineering (IGSSE) (C.H., M.P.M., and S.E.), and the Bio21 Molecular Science and Biotechnology Institute (M.P.M.). Disclosure of potential conflict of interest: L. M. Roesner has received project funding from Novartis and Almirall. C. Schlapbach has received honoraria as adviser or speaker for AbbVie, Almirall, BMS, Incyte, LEO Pharma, Lilly, Kiowa Kirin, Novartis, Pfizer, and Sanofi; and has received research funding from PPM Services A. Thorsti Møller Rønnstad has received research funding from the Department of Clinical Medicine, Copenhagen University, and the Kgl Hofbuntmager Aage Bangs Foundation. J. P. Thyssen has served as advisor for AbbVie, Almirall, Arena Pharmaceuticals, Coloplast, OM Pharma, Aslan Pharmaceuticals, Union Therapeutics, Eli Lilly, Pfizer, Regeneron, and Sanofi-Genzyme; has served as speaker for AbbVie, Almirall, Eli Lilly, Pfizer, Regeneron, and Sanofi Genzyme; and has received research grants from Pfizer, Regeneron, and Sanofi Genzyme; and has, since May 2023, been employed at LEO Pharma, where he holds stock options.