Stefanie Schärli, Fabian Luther, Jeremy Di Domizio, Christina Hillig, Susanne Radonjic-Hoesli, Kathrin Thormann, Dagmar Simon, Amalie Thorsti Møller Rønnstad, Iben Frier Ruge, Blaine G Fritz, Thomas Bjarnsholt, Angela Vallone, Sanja Kezic, Michael P Menden, Lennart M Roesner, Thomas Werfel, Jacob P Thyssen, Stefanie Eyerich, Michel Gilliet, Nicole L Bertschi, Christoph Schlapbach
{"title":"在特应性皮炎中，IL-9 使人类 Th2 细胞对促炎 IL-18 信号敏感。","authors":"Stefanie Schärli, Fabian Luther, Jeremy Di Domizio, Christina Hillig, Susanne Radonjic-Hoesli, Kathrin Thormann, Dagmar Simon, Amalie Thorsti Møller Rønnstad, Iben Frier Ruge, Blaine G Fritz, Thomas Bjarnsholt, Angela Vallone, Sanja Kezic, Michael P Menden, Lennart M Roesner, Thomas Werfel, Jacob P Thyssen, Stefanie Eyerich, Michel Gilliet, Nicole L Bertschi, Christoph Schlapbach","doi":"10.1016/j.jaci.2024.10.027","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>To decipher the role of IL-18 in Th2 responses in blood and skin of AD patients.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>IL-18Rα<sup>+</sup> 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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4000,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"IL-9 sensitizes human Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis.\",\"authors\":\"Stefanie Schärli, Fabian Luther, Jeremy Di Domizio, Christina Hillig, Susanne Radonjic-Hoesli, Kathrin Thormann, Dagmar Simon, Amalie Thorsti Møller Rønnstad, Iben Frier Ruge, Blaine G Fritz, Thomas Bjarnsholt, Angela Vallone, Sanja Kezic, Michael P Menden, Lennart M Roesner, Thomas Werfel, Jacob P Thyssen, Stefanie Eyerich, Michel Gilliet, Nicole L Bertschi, Christoph Schlapbach\",\"doi\":\"10.1016/j.jaci.2024.10.027\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>To decipher the role of IL-18 in Th2 responses in blood and skin of AD patients.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>IL-18Rα<sup>+</sup> 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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":14936,\"journal\":{\"name\":\"Journal of Allergy and Clinical Immunology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":11.4000,\"publicationDate\":\"2024-11-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Allergy and Clinical Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jaci.2024.10.027\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ALLERGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jaci.2024.10.027","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
IL-9 sensitizes human Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis.
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.
期刊介绍：
The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.
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