Abstract
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-15Rα expression as well as IL-15 trans-presentation by activating NF-κB 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.
Keywords:
CD8(+) T cell; IL-15; Keratinocyte; Oxidative stress; Vitiligo.
Copyright © 2019 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Inflammatory Agents / pharmacology
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Betamethasone / analogs & derivatives
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Betamethasone / pharmacology
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / metabolism*
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Coculture Techniques
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Drug Combinations
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Gene Expression Regulation
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Humans
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Hydrogen Peroxide / metabolism
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Interleukin-15 / genetics*
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Interleukin-15 / metabolism
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Janus Kinase 1 / genetics*
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Janus Kinase 1 / metabolism
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Keratinocytes / drug effects
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Keratinocytes / metabolism*
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Keratinocytes / pathology
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Lymphocyte Activation / drug effects
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Melanocytes / drug effects
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Melanocytes / metabolism
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Melanocytes / pathology
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Oxidative Stress
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Primary Cell Culture
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Interleukin-15 / antagonists & inhibitors
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Receptors, Interleukin-15 / genetics
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Receptors, Interleukin-15 / metabolism
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STAT3 Transcription Factor / genetics*
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Transcription Factor RelA / antagonists & inhibitors
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism
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Vitiligo / genetics*
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Vitiligo / metabolism
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Vitiligo / pathology
Substances
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Anti-Inflammatory Agents
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Drug Combinations
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IL15 protein, human
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IL15RA protein, human
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Interleukin-15
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RNA, Small Interfering
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Receptors, Interleukin-15
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STAT3 Transcription Factor
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STAT3 protein, human
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Transcription Factor RelA
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betamethasone dipropionate, betamethasone sodium phosphate drug combination
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Betamethasone
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Hydrogen Peroxide
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JAK1 protein, human
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Janus Kinase 1