Lymphatic Dysfunction Exacerbates Cutaneous Tumorigenesis and Psoriasis-Like Skin Inflammation through Accumulation of Inflammatory Cytokines
Lymphatic Dysfunction Exacerbates Cutaneous Tumorigenesis and Psoriasis-Like Skin Inflammation through Accumulation of Inflammatory Cytokines
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DOI：
10.1016/j.jid.2021.05.039
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发表时间：
2022-05-19
影响因子：
6.5
通讯作者：
Sato, Shinichi
中科院分区：
文献类型：
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作者：
Boki, Hikari;Kimura, Takayuki;Sato, Shinichi
淋巴转运在协调局部免疫反应中起重要作用。然而，体内淋巴流受损的生物学效应尚未完全了解。在这项研究中，我们研究了淋巴系统在皮肤癌发生和银屑病样炎症中的作用，使用k-cyclin转基因（kCYC（+/-））小鼠，表现出严重的淋巴功能障碍。与野生型小鼠相比，kCYC（+/-）小鼠在两阶段皮肤癌发生模型中显示出增加的肿瘤生长，并且在咪喹莫特诱导的银屑病样皮肤炎症中显示出严重的临床评分。虽然局部应用12-O-十四酰基佛波醇-13-乙酸酯或咪喹莫特后，kCYC（+/-）和野生型小鼠皮肤中炎性细胞因子的mRNA水平相当，但两种模型中kCYC（+/-）小鼠中炎性细胞因子（如IL-17 A、IL-22和IL-23）的蛋白水平均显著上调。结论：kCYC（+/-）小鼠表皮角质形成细胞中信号转导子和转录激活子3通路及NF-κ B信号转导增强。这些结果表明，kCYC（+/-）小鼠的淋巴功能障碍引起炎症细胞因子的积累，导致两阶段皮肤癌的恶化和咪喹莫特诱导的银屑病样皮肤炎症。这些发现增加了对继发性恶性肿瘤和皮肤病的临床问题的深入了解，
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-kappa B 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 indermatoses that occur with