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

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

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

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 BertschiChristoph Schlapbach^*

^*Corresponding author af dette arbejde

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	The Journal of allergy and clinical immunology
ISSN	0091-6749
DOI	https://doi.org/10.1016/j.jaci.2024.10.027
Status	E-pub ahead of print - 7 nov. 2024

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10.1016/j.jaci.2024.10.027

Citationsformater

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., ... Schlapbach, C. (2024). IL-9 sensitizes human Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis. The Journal of allergy and clinical immunology. Advance online publication. https://doi.org/10.1016/j.jaci.2024.10.027

Schärli, S, Luther, F, Di Domizio, J, Hillig, C, Radonjic-Hoesli, S, Thormann, K, Simon, D, Møller Rønnstad, AT, Ruge, IF, Fritz, BG, Bjarnsholt, T, Vallone, A, Kezic, S, Menden, MP, Roesner, LM, Werfel, T, Thyssen, JP, Eyerich, S, Gilliet, M, Bertschi, NL & Schlapbach, C 2024, 'IL-9 sensitizes human Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis', The Journal of allergy and clinical immunology. https://doi.org/10.1016/j.jaci.2024.10.027

@article{e54d33d503e04423801130457e1471fa,

title = "IL-9 sensitizes human Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis",

abstract = "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.",

author = "Stefanie Sch{\"a}rli and Fabian Luther and {Di Domizio}, Jeremy and Christina Hillig and Susanne Radonjic-Hoesli and Kathrin Thormann and Dagmar Simon and {M{\o}ller R{\o}nnstad}, {Amalie Thorsti} and Ruge, {Iben Frier} and Fritz, {Blaine G} and Thomas Bjarnsholt and Angela Vallone and Sanja Kezic and Menden, {Michael P} and Roesner, {Lennart M} and Thomas Werfel and Thyssen, {Jacob P} and Stefanie Eyerich and Michel Gilliet and Bertschi, {Nicole L} and Christoph Schlapbach",

note = "Copyright {\textcopyright} 2024. Published by Elsevier Inc.",

year = "2024",

month = nov,

day = "7",

doi = "10.1016/j.jaci.2024.10.027",

language = "English",

journal = "The Journal of allergy and clinical immunology",

issn = "0091-6749",

publisher = "Mosby, Inc",

}

TY - JOUR

T1 - IL-9 sensitizes human Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis

AU - Schärli, Stefanie

AU - Luther, Fabian

AU - Di Domizio, Jeremy

AU - Hillig, Christina

AU - Radonjic-Hoesli, Susanne

AU - Thormann, Kathrin

AU - Simon, Dagmar

AU - Møller Rønnstad, Amalie Thorsti

AU - Ruge, Iben Frier

AU - Fritz, Blaine G

AU - Bjarnsholt, Thomas

AU - Vallone, Angela

AU - Kezic, Sanja

AU - Menden, Michael P

AU - Roesner, Lennart M

AU - Werfel, Thomas

AU - Thyssen, Jacob P

AU - Eyerich, Stefanie

AU - Gilliet, Michel

AU - Bertschi, Nicole L

AU - Schlapbach, Christoph

PY - 2024/11/7

Y1 - 2024/11/7

N2 - 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.

AB - 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.

U2 - 10.1016/j.jaci.2024.10.027

DO - 10.1016/j.jaci.2024.10.027

M3 - Journal article

C2 - 39521283

SN - 0091-6749

JO - The Journal of allergy and clinical immunology

JF - The Journal of allergy and clinical immunology

ER -

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

Abstract

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