银屑病是一种发病机制尚不清楚且治疗需求未得到满足的炎症性皮肤病。旨在探讨衰老的CD4 T细胞在银屑病皮损形成中的作用，并探讨衰老药物在银屑病治疗中的应用。我们探讨了银屑病经典标志物p16INK4a和p21的表达水平。人类银屑病病变和咪喹莫特 (IMQ) 诱导的银屑病病变的 CD4 T 细胞中的细胞衰老。我们使用 B 细胞淋巴瘤 2 (BCL-2) 抑制剂 ABT-737 制备了 senolytic 凝胶，并评估了其治疗银屑病的疗效。使用多谱免疫组织化学 (mIHC) 染色，我们检测到 CD4 T 细胞中 p16INK4a 和 p21 的表达水平增加来自银屑病病变。局部应用 ABT-737 凝胶后，观察到 IMQ 引起的银屑病皮损明显减轻，病理改变较轻微。从机制上讲，根据 mIHC 测定，ABT-737 凝胶显着降低了 IMQ 诱导的银屑病病变中衰老细胞的百分比、T 细胞受体 (TCR) α 和 β 链的表达以及 Tet 甲基胞嘧啶双加氧酶 2 (Tet2) 的表达，高-TCR库的通量测序和RT-qPCR，分别。此外，在 IMQ 诱导的银屑病模型中，CD4creTet2f/f 小鼠的银屑病病变严重程度比 Tet2f/f 小鼠轻。我们揭示了衰老的 CD4 T 细胞在银屑病发展中的作用，并强调了局部 ABT 的治疗潜力737 凝胶通过消除衰老细胞、调节 TCR αβ 库和调节 TET2-Th17 细胞通路来治疗牛皮癣。版权所有 © 2024 日本皮肤病研究学会。由 Elsevier B.V. 出版。保留所有权利。

Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs.To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis.We explored the expression levels of p16INK4a and p21, classical markers of cellular senescence, in CD4+ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis.Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a and p21 in CD4+ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and β chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model.We revealed the roles of senescent CD4+ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αβ repertoire, and regulation of the TET2-Th17 cell pathway.Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.