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Schärli, S.* ; Luther, F.* ; Di Domizio, J.* ; Hillig, C. ; Radonjic-Hoesli, S.* ; Thormann, K.* ; Simon, D.* ; Møller Rønnstad, A.T.* ; Ruge, I.F.* ; Fritz, B.G.* ; Bjarnsholt, T.* ; Vallone, A.* ; Kezic, S.* ; Menden, M.P. ; Roesner, L.M.* ; Werfel, T.* ; Thyssen, J.P.* ; Eyerich, S. ; Gilliet, M.* ; Bertschi, N.L.* ; Schlapbach, C.*

IL-9 sensitizes human Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis.

J. Allergy Clin. Immunol., DOI: 10.1016/j.jaci.2024.10.027 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
BACKGROUND: T helper 2 (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 as it is implicated in AD pathogenesis and has the capacity to activate T cells. OBJECTIVE: To decipher the role of IL-18 in Th2 responses in blood and skin of AD patients. METHODS: PBMCs and skin biopsies from AD patients and healthy donors were used. Functional assays were performed ex vivo using stimulation or blocking experiments. Analysis was performed using flow cytometry, bead-based multiplex assays, RT-qPCR, RNA-seq, western blotting, 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 co-stimulation 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Il-9 Receptor (il-9r) ; Atopic Dermatitis (ad) ; Interleukin-1 Receptor-associated Kinase 4 (irak4) ; Interleukin-18 (il-18) ; Interleukin-18 Receptor (il-18r) ; Interleukin-9 (il-9) ; Pathogenic Th2 Cells (pth2) ; Upstream Regulator Of Th2 Cells
ISSN (print) / ISBN 0091-6749
e-ISSN 1097-6825
Journal The journal of allergy and clinical immunology
Publisher Elsevier
Publishing Place Amsterdam [u.a.]
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Institute for Allergy Research (IAF)