Abstract：
BACKGROUND: Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs.
OBJECTIVE: To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：银屑病是一种发病机制不明确且治疗需求未得到满足的炎症性皮肤病。
目的：探讨衰老CD4+T细胞在银屑病皮损形成中的作用，探讨抗衰老药物在银屑病治疗中的应用。
方法：我们探索了细胞衰老的经典标志物p16INK4a和p21的表达水平，在人银屑病皮损和咪喹莫特（IMQ）诱导的银屑病皮损的CD4T细胞中。我们使用B细胞淋巴瘤2（BCL-2）抑制剂ABT-737制备了抗衰老凝胶，并评估了其治疗牛皮癣的疗效。
结果：使用多光谱免疫组织化学（mIHC）染色，我们检测到银屑病皮损CD4+T细胞中p16INK4a和p21的表达水平升高。局部应用ABT-737凝胶后，观察到IMQ诱导的银屑病病变的显着缓解，病理改变较温和。机械上,ABT-737凝胶显着降低衰老细胞的百分比，T细胞受体（TCR）α和β链的表达，和Tet甲基胞嘧啶双加氧酶2（Tet2）在IMQ诱导的银屑病皮损中的表达，根据mIHC确定，TCR库的高通量测序，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。
结论：我们揭示了衰老CD4+T细胞在发展银屑病中的作用，并强调了局部ABT-737凝胶通过消除衰老细胞治疗银屑病的治疗潜力。TCRαβ库的调制，和TET2-Th17细胞途径的调节。
目的：探讨衰老CD4+T细胞在银屑病皮损形成中的作用，探讨抗衰老药物在银屑病治疗中的应用。
方法：我们探索了细胞衰老的经典标志物p16INK4a和p21的表达水平，在人银屑病皮损和咪喹莫特（IMQ）诱导的银屑病皮损的CD4T细胞中。我们使用B细胞淋巴瘤2（BCL-2）抑制剂ABT-737制备了抗衰老凝胶，并评估了其治疗牛皮癣的疗效。
结果：使用多光谱免疫组织化学（mIHC）染色，我们检测到银屑病皮损CD4+T细胞中p16INK4a和p21的表达水平升高。局部应用ABT-737凝胶后，观察到IMQ诱导的银屑病病变的显着缓解，病理改变较温和。机械上,ABT-737凝胶显着降低衰老细胞的百分比，T细胞受体（TCR）α和β链的表达，和Tet甲基胞嘧啶双加氧酶2（Tet2）在IMQ诱导的银屑病皮损中的表达，根据mIHC确定，TCR库的高通量测序，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。
结论：我们揭示了衰老CD4+T细胞在发展银屑病中的作用，并强调了局部ABT-737凝胶通过消除衰老细胞治疗银屑病的治疗潜力。TCRαβ库的调制，和TET2-Th17细胞途径的调节。
