Oxidative stress drives CD8+T cells skin trafficking in vitiligo via CXCL16 upregulation by activating the unfolded protein response in keratinocytes

Publication date: Available online 5 November 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Shuli Li, Guannan Zhu, Yuqi Yang, Zhe Jian, Sen Guo, Wei Dai, Qiong Shi, Rui Ge, Jingjing Ma, Ling Liu, Kai Li, Qi Luan, Gang Wang, Tianwen Gao, Chunying Li
BackgroundIn vitiligo, elevated reactive oxygen species (ROS) have been proven as 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 e.g. keratinocytes and the following immune events. CXCL16 is constitutively expressed in keratinocytes and recently found to mediate homing of CD8⁺T cells in human skin.ObjectiveTo explicate the effect of oxidative stress on human keratinocyte and its capacity to drive CD8⁺T cell trafficking via CXCL16 regulation.MethodsWe first detected putative T cells skin homing chemokines and ROS level in vitiligo serum and lesions. The production of candidate chemokines was detected by qRT-PCR and ELISA in keratinocytes exposed to H2O2. Furthermore, mediators involved were analyzed by qRT-PCR, western blot, ELISA and immunofluorescence. Next, we tested the chemotactic migration of vitiligo CD8⁺T cells mediated by CXCL16–CXCR6 pair by transwell assay.ResultsCXCL16 expression increased and showed a positive correlation with oxidative stress level in vitiligo serum and lesions. The H2O2–induced CXCL16 expression was due to the activation of 2 unfolded protein response pathways, PERK–eIF2α and IRE1α–XBP1. CXCL16 produced by stressed keratinocytes induced migration of CXCR6⁺CD8⁺T cells derived from vitiligo patients. CXCR6⁺CD8⁺T cells skin infiltration is accompanied by melanocytes loss in vitiligo lesions.ConclusionOur study demonstrated that CXCL16–CXCR6 mediates CD8⁺T cell skin trafficking under oxidative stress in vitiligo. The CXCL16 expression in human keratinocytes induced by ROS is, at least partially, by UPR activation.

Teaser

Oxidative stress drives CD8⁺T cell trafficking via CXCL16–CXCR6 interaction in vitiligo, and the CXCL16 expression in stressed keratinocytes is mediated by UPR activation.


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