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Lymphatic Dysfunction Exacerbates Cutaneous Tumorigenesis and Psoriasis-Like Skin Inflammation through Accumulation of Inflammatory Cytokines

  • Author Footnotes
    6 These authors contributed equally to this work.
    Hikari Boki
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
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  • Author Footnotes
    6 These authors contributed equally to this work.
    Takayuki Kimura
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
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  • Tomomitsu Miyagaki
    Correspondence
    Correspondence: Tomomitsu Miyagaki, Department of Dermatology, School of Medicine, St. Marianna University, 2-16-1 Sugao, Miyamae-ku, Kawasaki-shi, Kanagawa 216-8511, Japan.
    Affiliations
    Department of Dermatology, St. Marianna University School of Medicine, Kanagawa, Japan
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  • Hiraku Suga
    Affiliations
    Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
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  • Andrew Blauvelt
    Affiliations
    Oregon Medical Research Center, Portland, Oregon, USA
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  • Hitoshi Okochi
    Affiliations
    Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
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  • Makoto Sugaya
    Affiliations
    Department of Dermatology, School of Medicine, International University of Health and Welfare, Chiba, Japan
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  • Shinichi Sato
    Affiliations
    Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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  • Author Footnotes
    6 These authors contributed equally to this work.
Published:November 12, 2021DOI:https://doi.org/10.1016/j.jid.2021.05.039
      Lymphatic transport plays an important role in coordinating local immune responses. However, the biologic effects of impaired lymphatic flow in vivo are not fully understood. In this study, we investigated the roles of the lymphatic system in skin carcinogenesis and psoriasis-like inflammation using k-cyclin transgenic (kCYC+/−) mice, which demonstrate severe lymphatic dysfunction. kCYC+/− mice showed augmented tumor growth in the two-stage skin carcinogenesis model and severe clinical scores in imiquimod-induced psoriasis-like skin inflammation compared with wild-type mice. Although mRNA levels of inflammatory cytokines in skin after topical application of 12-O-tetradecanoylphorbol-13-acetate or imiquimod were comparable between kCYC+/– and wild-type mice, protein levels of inflammatory cytokines, such as IL-17A, IL-22, and IL-23, were significantly upregulated in kCYC+/– mice in both models. Consistently, signal transducer and activator of transcription 3 pathway and NF-κB signaling were augmented in epidermal keratinocytes in kCYC+/– mice. These results suggest that lymphatic dysfunction in kCYC+/– mice caused accumulation of inflammatory cytokines, leading to the exacerbation of two-stage skin carcinogenesis and imiquimod-induced psoriasis-like skin inflammation. These findings add insight into the clinical problems of secondary malignancies and inflammatory dermatoses that may occur with extremity lymphedema.

      Abbreviations:

      DC (dendritic cell), DMBA (7,12-dimethylbenz(a)anthracene), IMQ (imiquimod), KC (keratinocyte), kCYC+/− (k-cyclin transgenic), LC (Langerhans cell), LN (lymph node), SCC (squamous cell carcinoma), STAT (signal transducer and activator of transcription), TPA (12-O-tetradecanoylphorbol-13-acetate), WT (wild-type)
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