Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, Hunan Key Laboratory of Medical Epigenetics, China.
Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, China.
Oxid Med Cell Longev. 2022 Feb 16;2022:6732972. doi: 10.1155/2022/6732972. eCollection 2022.
Loss of melanocytes induced by activated CD8 T cells is the pathological hallmark of vitiligo. Melanocyte-specific CD8 T cells are recruited to the skin via chemokines, thereby releasing perforin, granzyme, and other cytotoxic substances that destroy the melanocytes. However, the mechanism of CD8 T cells to adhere to melanocytes is unknown. Previous transcriptome sequencing results published by our group showed that the occluding ( gene was significantly upregulated in CD8 T cells from skin lesions of vitiligo. Occludin is a crucial component of the tight junction between cells; in cells without tight junction, occludin mediates the adhesion of two cells in the form of a self-ligand. This study demonstrated that gene expression was elevated in the CD8 T cells of vitiligo patients, and occludin mediates the adherence of CD8 T cells to melanocytes. Besides, pathological changes in vitiligo skin lesions reveal that CD8 T cells continuously persist in the skin lesions, which is related to the persistence of the disease. In this regard, we found that fibroblasts from vitiligo patients significantly express occludin, which may participate in the continuous retention of CD8 T cells in the skin lesions. The pathogenesis of vitiligo is closely related to oxidative stress, and our data suggest that overexpression of hypoxia-inducible factor-1 (HIF-1) increases the expression of occludin. Besides, ChIP-qPCR of CD8 T cells revealed that HIF-1 directly binds to the promoter. Thus, occludin upregulation promotes the adhesion of CD8 T cells and melanocytes via the HIF-1 signaling pathway. Our study results suggested a critical role for in the occurrence, progression, and maintenance of vitiligo. Therefore, inhibiting the expression of gene may be a potential targeted treatment strategy.
由激活的 CD8 T 细胞引起的黑色素细胞丧失是白癜风的病理标志。黑色素细胞特异性 CD8 T 细胞通过趋化因子募集到皮肤，从而释放穿孔素、颗粒酶和其他破坏黑色素细胞的细胞毒性物质。然而，CD8 T 细胞黏附黑色素细胞的机制尚不清楚。我们小组之前发表的转录组测序结果表明，在白癜风皮损的 CD8 T 细胞中，occludin（基因显著上调。occludin 是细胞间紧密连接的关键组成部分；在没有紧密连接的细胞中，occludin 以自配体的形式介导两个细胞的黏附。本研究表明，白癜风患者的 CD8 T 细胞中基因表达上调，occludin 介导 CD8 T 细胞与黑色素细胞的黏附。此外，白癜风皮损的病理变化表明，CD8 T 细胞持续存在于皮损中，这与疾病的持续存在有关。在这方面，我们发现白癜风患者的成纤维细胞显著表达 occludin，这可能参与了 CD8 T 细胞在皮损中的持续保留。白癜风的发病机制与氧化应激密切相关，我们的数据表明，缺氧诱导因子-1（HIF-1）的过表达增加了 occludin 的表达。此外，CD8 T 细胞的 ChIP-qPCR 显示 HIF-1 直接结合到 启动子上。因此，occludin 的上调通过 HIF-1 信号通路促进 CD8 T 细胞和黑色素细胞的黏附。我们的研究结果表明，在白癜风的发生、发展和维持过程中，发挥着关键作用。因此，抑制基因的表达可能是一种潜在的靶向治疗策略。
