IL-23 from Langerhans Cells Is Required for the Development of Imiquimod-Induced Psoriasis-Like Dermatitis by Induction of IL-17A-Producing γδ T Cells

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IL-23 from Langerhans Cells Is Required for the Development of Imiquimod-Induced Psoriasis-Like Dermatitis by Induction of IL-17A-Producing γδ T Cells Ryutaro Yoshiki, Kenji Kabashima, Tetsuya Honda, Satoshi Nakamizo, Yu Sawada, Kazunari Sugita, Haruna Yoshioka, Shun Ohmori, Bernard Malissen, Yoshiki Tokura, Motonobu Nakamura Journal of Investigative Dermatology Volume 134, Issue 7, Pages 1912-1921 (July 2014) DOI: 10.1038/jid.2014.98 Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Langerhans cell–depleted mice show decreased IMQ-induced psoriasis-like skin inflammation. Langerin+ cells were depleted by DT in Langerin-DTR–knocked-in mice. Langerin+ dDCs, but not Langerhans cells, repopulated in the skin 10 days later. C57BL/6J mice or Langerin-DTR–knocked-in mice were treated daily with IMQ cream or control cream application on both ears for 5 consecutive days. (a) H&E-stained and immunohistochemical staining of Stat3, Ki-67 sections. (b) The ear swelling at day 6. (c) The numbers of Stat3- or Ki67-positive keratinocytes. Data are representative of four independent experiments and each group consisted of more than four mice. *P<0.05 between indicated groups. Normal bar=200 μm, dotted bar=100 μm. dDCs, dermal dendritic cells; DT, diphtheria toxin; DTR, DT receptor; H&E, hematoxylin and eosin; IMQ, imiquimod. Journal of Investigative Dermatology 2014 134, 1912-1921DOI: (10.1038/jid.2014.98) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 IMQ application induces cytokine mRNA production in skin. IMQ cream was applied on both ears of LC/Langerin+ d DC–depleted mice or LC-depleted mice for 5 consecutive days. Real-time PCR analysis revealed that LC-depleted skin showed less expression of (a) IL-12p19, (b) IL-12/23p40, (c) IL-17A, (d) IL-22, and (e) TNF-α mRNA after IMQ application. Error bars indicate s.d. based on a single, pooled treatment group that was divided into three wells for RT-PCR measurement. Similar results were obtained in two independent experiments and each group consisted of more than four mice. *P<0.05 between indicated groups. DC, dendritic cell; DT, diphtheria toxin; IMQ, imiquimod; LC, Langerhans cell; TNF, tumor necrosis factor. Journal of Investigative Dermatology 2014 134, 1912-1921DOI: (10.1038/jid.2014.98) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 LCs produce IL-23 after application of IMQ. IMQ cream was applied to mice ears for 5 consecutive days and whole-skin suspension was analyzed by real-time PCR. (a) TLR7 was expressed on Langerin− dDCs by application of IMQ. (b, c) Whole-skin suspension was stained with PE-conjugated IL-23 for flow cytometry. LC-depleted skin did not show an increase in the number of IL-23-producing cells. Data points represent individual frequencies. (d, e) CD45+ MHC class II–positive cells were gated by EpCAM and Langerin. Other CD45-positive cells were gated by γδTCR and Ly-6G (Gr1). Only LCs showed IL-23 production by IMQ application (f, g). Data are representative of four independent experiments and each group consisted of more than five mice. dDCs, dermal dendritic cells; DT, diphtheria toxin; IMQ, imiquimod; KCs, keratinocytes; LCs, Langerhans cells; MHC, major histocompatibility complex; NS, not significant; TLR, Toll-like receptor. Journal of Investigative Dermatology 2014 134, 1912-1921DOI: (10.1038/jid.2014.98) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 IL-17A-producing CCR6+ γδ T cells are reduced in a Langerhans cell (LC)-depleted and imiquimod (IMQ)-applied epidermis. γδ TCR-positive cells in the epidermis and dermis. Expression of γδTCR, CD4, and intracellular IL-17A was examined in diphtheria toxin (DT)± and IMQ-applied skin by flow cytometry. (a–d) IMQ application induced the IL-17A-producing γδTCR mid+ cells in the epidermis and LC depletion suppressed the induction of IL-17A γδTCR mid+ cells. There was no change in the recruitment of IL-17A-producing γδTCR mid+ cells in the dermis. (e–h) There was no significant increase in the number of IL-17A-producing CD4+ cells in the epidermis, but IL-17A-producing CD4+ cells increased in the dermis. Data are representative of four independent experiments and each group consisted of more than five mice. NS, not significant. *P<0.05 between indicated groups. Journal of Investigative Dermatology 2014 134, 1912-1921DOI: (10.1038/jid.2014.98) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 IL-23-producing LCs migrate to the draining lymph nodes and LCs are indispensable for induction of IL-17A-producing γδ T cells. Regional lymph nodes from IMQ-applied mice were analyzed by flow cytometry. (a, c) IMQ application induces IL-23-producing MHC class II+ cells in the draining lymph nodes, but LC-depleted mice did not show induction of IL-23-producing MHC class II+ cells. (b) IL-23-producing cells in the draining lymph node express EpCAM and Langerin, the markers for LCs. (d–g) Increase in the number of IL-17A-producing γδ T cells and CD4+ T cells in the draining lymph node was suppressed by the depletion of LCs. Data are representative of four independent experiments and each group consisted of more than five mice. DT, diphtheria toxin; IMQ, imiquimod; LCs, Langerhans cells; MHC, major histocompatibility complex. *P<0.05. Journal of Investigative Dermatology 2014 134, 1912-1921DOI: (10.1038/jid.2014.98) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Skin-derived IL-23-producing LCs have a critical role in IMQ-induced skin inflammation. (a) Recipient WT C57BL/6J mice or IL-23 KO mice (C57BL/6J background) underwent 9 Gy total body irradiation on day -1, and received bone marrow single-cell suspensions from WT C57BL/6J mice or IL-23 KO mice on day 0. LCs remained in the skin even after the irradiation, whereas LN cells of the recipients were derived from donors. (b) Two months after transplantation, IMQ cream was applied on each chimera mouse and increase in ear thickness was measured on day 6. Ear thickness decreased when recipients were IL23KO mice. Data are representative of four independent experiments and each group consisted of more than five mice. IMQ, imiquimod; KO, knockout; LCs, Langerhans cells; LN, lymph node; NS, not significant; WT, wild type. *P<0.05. Journal of Investigative Dermatology 2014 134, 1912-1921DOI: (10.1038/jid.2014.98) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions