Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 139, Issue -, Pages 80-91Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2019.05.011
Keywords
IL-15; Oxidative stress; Keratinocyte; CD8+T cell; Vitiligo
Funding
- National Natural Science Foundation of China [91742201, 81803112, 81773315, 81602764, 81602750]
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Oxidative stress and effector memory CD8(+) T cells have been greatly implicated in vitiligo pathogenesis. However, the crosstalk between these two crucial pathogenic factors has been merely investigated. IL-15 has been regarded as an important cytokine exerting its facilitative effect on memory CD8(+) T cells function in various autoimmune diseases. In the present study, we initially discovered that the IL-15 expression was significantly increased in vitiligo epidermis and highly associated with epidermal H2O2 content. In addition, epidermal IL-15 expression was mainly derived from keratinocytes. Then, we showed that oxidative stress promoted IL-15 and IL-15R alpha expression as well as IL-15 trans-presentation by activating NF-kappa B signaling in keratinocytes. What's more, the trans-presented IL-15, rather than the secreted one, was accounted for the potentiation of CD8(+) TEMs activation. We further investigated the mechanism underlying trans-presented IL-15 in potentiating CD8(+) TEMs activation and found that the blockage of IL-15-JAK-STAT signaling could be a potent therapeutic approach. Taken together, our results demonstrate that oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to the activation of CD8(+) TEMs, providing a novel mechanism by which oxidative stress initiates autoimmunity in vitiligo.
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