Oxidative stress drives CD8+ T-cell skin trafficking in patients with vitiligo through CXCL16 upregulation by activating the unfolded protein response in keratinocytes
Oxidative stress drives CD8+ T-cell skin trafficking in patients with vitiligo through CXCL16 upregulation by activating the unfolded protein response in keratinocytes
复制标题
氧化应激通过激活角质形成细胞中的未折叠蛋白反应，通过上调 CXCL16 驱动白癜风患者的 CD8( ) T 细胞皮肤运输
DOI：
10.1016/j.jaci.2016.10.013
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发表时间：
2017-07-01
影响因子：
14.2
通讯作者：
Li, Chunying
中科院分区：
文献类型：
--
作者：
Li, Shuli;Zhu, Guannan;Li, Chunying
背景：在白癜风患者中，活性氧簇(ROS)水平的升高已被证明是黑素细胞疾病发生和发展的关键因素。然而，关于ROS对参与异常微环境的其他细胞的影响，如角质形成细胞和随后的免疫事件，人们知之甚少。目的：探讨氧化应激对人皮肤角质形成细胞的影响及其对CD8(+)T细胞转运的影响。方法：我们首先检测了白癜风患者血清和皮损中可能存在的T细胞归巢趋化因子和ROS。用实时定量聚合酶链式反应和酶联免疫吸附试验检测过氧化氢作用下角质形成细胞中趋化因子的产生。采用实时定量聚合酶链式反应、Western blotting、酶联免疫吸附试验和免疫荧光等方法对所涉及的介体进行分析。结果：白癜风患者血清和皮损中CD8(+)T细胞的表达水平与氧化应激水平呈正相关。H_2O_2诱导的CXCL16的表达是由于两条未折叠的蛋白应答通路的激活：PKR样ERK-真核启动因子2α和肌醇需要酶1α-X-box结合蛋白1。白癜风患者皮损中CXCR6+CD8+T细胞皮肤浸润伴有黑素细胞丢失。结论：CXCL16-CXCR6介导了氧化应激条件下白癜风患者CD8+T细胞皮肤转运。ROS诱导的角质形成细胞中CXCL16的表达至少部分是由未折叠蛋白反应激活引起的。
Background: In patients with vitiligo, an increased reactive oxygen species (ROS) level has been proved to be a key player during disease initiation and progression in melanocytes. Nevertheless, little is known about the effects of ROS on other cells involved in the aberrant microenvironment, such as keratinocytes and the following immune events. CXCL16 is constitutively expressed in keratinocytes and was recently found to mediate homing of CD8(+) T cells in human skin.Objective: We sought to explicate the effect of oxidative stress on human keratinocytes and its capacity to drive CD8(+) T-cell trafficking through CXCL16 regulation.Methods: We first detected putative T-cell skin-homing chemokines and ROS in serum and lesions of patients with vitiligo. The production of candidate chemokines was detected by using quantitative real-time PCR and ELISA in keratinocytes exposed to H2O2. Furthermore, the involved mediators were analyzed by using quantitative real-time PCR, Western blotting, ELISA, and immunofluorescence. Next, we tested the chemotactic migration of CD8(+) T cells from patients with vitiligo mediated by the CXCL16-CXCR6 pair using the transwell assay.Results: CXCL16 expression increased and showed a positive correlation with oxidative stress levels in serum and lesions of patients with vitiligo. The H2O2-induced CXCL16 expression was due to the activation of 2 unfolded protein response pathways: kinase RNA (PKR)-like ER kinase-eukaryotic initiation factor 2 alpha and inositol-requiring enzyme 1 alpha-X-box binding protein 1. CXCL16 produced by stressed keratinocytes induced migration of CXCR6+ CD8+ T cells derived from patients with vitiligo. CXCR6+ CD8+ T-cell skin infiltration is accompanied by melanocyte loss in lesions of patients with vitiligo.Conclusion: Our study demonstrated that CXCL16-CXCR6 mediates CD8+ T-cell skin trafficking under oxidative stress in patients with vitiligo. The CXCL16 expression in human keratinocytes induced by ROS is, at least in part, caused by unfolded protein response activation.