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.
Department of Dermatology, St. Marianna University School of Medicine, Kanagawa, Japan.
J Invest Dermatol. 2022 Jun;142(6):1692-1702.e3. doi: 10.1016/j.jid.2021.05.039. Epub 2021 Nov 13.
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.
淋巴转运在协调局部免疫反应中起着重要作用。然而，体内淋巴流动受损的生物学效应尚未完全被理解。在这项研究中，我们使用 k-cyclin 转基因（kCYC）小鼠研究了淋巴系统在皮肤癌发生和类银屑病炎症中的作用，kCYC 小鼠表现出严重的淋巴功能障碍。与野生型小鼠相比，kCYC 小鼠在二阶段皮肤致癌模型中表现出增强的肿瘤生长，并且在咪喹莫特诱导的类银屑病皮肤炎症中表现出严重的临床评分。尽管 kCYC 和野生型小鼠在局部应用 12-O-十四烷酰佛波醇-13-乙酸酯或咪喹莫特后皮肤中的炎症细胞因子 mRNA 水平相当，但两种模型中 kCYC 小鼠的炎症细胞因子（如 IL-17A、IL-22 和 IL-23）的蛋白水平显著上调。一致地，kCYC 小鼠表皮角质形成细胞中的信号转导和转录激活因子 3 通路和 NF-κB 信号被增强。这些结果表明，kCYC 小鼠的淋巴功能障碍导致炎症细胞因子的积累，从而加剧二阶段皮肤癌发生和咪喹莫特诱导的类银屑病皮肤炎症。这些发现为可能与四肢淋巴水肿相关的继发性恶性肿瘤和炎症性皮肤病的临床问题提供了新的见解。
