Original article
Oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to CD8+ T cells activation via JAK-STAT pathway in vitiligo

https://doi.org/10.1016/j.freeradbiomed.2019.05.011Get rights and content

Highlights

  • IL-15 links oxidative stress to immune response in vitiligo.

  • Oxidative stress increases IL-15 expression and trans-presentation in keratinocytes probably by NF-κB signaling.

  • Oxidative stress-induced IL-15 trans-presentation causes CD8+ TEMs activation via a cell-contact form in vitiligo.

  • Targeting the IL-15-JAK-STAT axis might shed new light on vitiligo treatment.

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.

Introduction

Vitiligo is a common skin depigmenting disorder with destruction of epidermal melanocyte that creates white spots and patches in the skin. It affects approximately 0.5%–2.0% in the populations worldwide [1,2], whereas to date there are no U.S. Food and Drug Administration-approved medical treatments of vitiligo patients [3,4]. Increasing evidence has revealed that oxidative stress and effector memory CD8+ T cells (CD8+ TEMs) contribute to melanocyte degeneration in vitiligo pathogenesis [[5], [6], [7]]. Our previous study demonstrated that oxidative stress could promote the expression and secretion of chemokines in keratinocytes and facilitate the migration of CD8+ TEMs to skin for melanocyte destruction [8]. However, the crosstalk between oxidative stress and the activation of CD8+ TEMs has not been sufficiently elucidated.

Interleukin-15 (IL-15) is a member of the four α-helix bundle family of cytokines sharing the cytokine receptor γ-chain (γc; also known as CD132) and the β-chain (IL-2/IL-15Rβ; also known as CD122) with the receptors for IL-2 [9]. Previous studies revealed that IL-15 was assembled with IL-15Rα (also known as CD215) as stable IL-15-IL-15Rα complexes in the endoplasmic reticulum (ER), then shuttled to the cell membrane of distressed cells [10]. Thus, IL-15 functions mainly in a cell contact-dependent manner through the trans-presentation of membrane-bound IL-15-IL-15Rα complexes [11]. Recent report also revealed the presence of soluble secreted IL-15-IL-15Rα complexes with prominent facilitative effect on immune cell function [12]. IL-15 potentiates JAK1-STAT3 and JAK3-STAT5 signaling pathways in immune cells, thus involving in the homeostasis and activation of immune response [13,14], especially the CD8+ T cell-dependent autoimmune diseases [15,16]. Accumulating evidence has demonstrated that some autoimmune disorders are correlated with IL-15 up-regulation, including rheumatoid arthritis, alopecia areata, celiac disease and inflammatory bowel disease, where dysregulated CD8+ T cell function greatly implicated [[15], [16], [17], [18]]. Intriguingly, CD122 (IL-2/IL-15Rβ) neutralizing antibody has the potential to provide durable repigmentation in mice with vitiligo [19]. However, the molecular mechanism underlying IL-15 expression and trans-presentation in the activation of CD8+ TEMs has not been investigated in vitiligo.

Multiple mechanisms have been documented the up-regulation of IL-15. To be specific, bacterial and viral infections-related innate signals such as Tax, double-stranded RNA and TLR signaling through MYD88 could induce IL-15 expression [[20], [21], [22]]. In addition, the expressions of nuclear factor-κB (NF-κB) and IFN regulatory factor 1 (IRF1) could be augmented in some stressed circumstances to obtain the transcriptional activation of IL-15 [[23], [24], [25]]. Nevertheless, whether oxidative stress-related signaling could contribute to potentiating IL-15 expression remains unknown. In response to oxidative stress, NF-κB could be activated to promote the expressions of chemokines and cytokines in vitiligo and many inflammatory diseases [8,26,27]. Given this, we hypothesized that oxidative stress may promote IL-15 up-regulation through NF-κB signaling and subsequently boost CD8+ TEMs function through trans-presentation of membrane-bound IL-15-IL-15Rα complexes and/or soluble secreted IL-15-IL-15Rα complexes, which was implicated in melanocyte destruction in vitiligo.

Section snippets

Patients and clinical samples

Peripheral blood and perilesional skin tissues were collected from patients diagnosed with non-segmental vitiligo based on clinical and histologic characteristics in the Department of Dermatology, Xijing Hospital of the Fourth Military Medical University. All the patients and the healthy volunteers were pair-matched for age and gender. The research protocols referring to human samples were performed according to the principles of the Declaration of Helsinki. The study was approved by the Ethics

Levels of IL-15 and H2O2 are increased in patients with vitiligo

First, we found that the mRNA level of IL-15 in the epidermis was significantly increased in vitiligo perilesional skins in comparison to the healthy controls (Fig. 1A). In addition, the increased IL-15 mRNA level was in prominent positive correlation with H2O2 accumulation in vitiligo perilesional skins, indicating the close association between oxidative stress and IL-15 expression (Fig. 1B and C). Furthermore, the immunofluorescence staining analysis displayed that IL-15 was remarkably

Discussion

In the present study, we first found IL-15 expression was significantly increased in keratinocytes in vitiligo epidermis and was closely related to the oxidative stress microenvironment. Then, our data proved that oxidative stress promoted IL-15 expression and trans-presentation in keratinocytes by activating NF-κB signaling. Subsequently, our data showed that oxidative stress-induced IL-15 trans-presentation in keratinocytes potentiated the activation and expression of cytotoxic proteins in CD8

Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 91742201, No. 81803112, No. 81773315, No. 81602764, No. 81602750).

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      Citation Excerpt :

      One study showed that IL15 causes the expression of NKG2D in memory CD8 + T Cells in skin with vitiligo, triggering the production of IFNγ and TNFα.89 Additionally, oxidative stress has been shown to induce IL15 transpresentation in keratinocytes, contributing to the activation of memory CD8 + T Cells through the activation of the JAK/STAT pathway (JAK1-STAT3 and JAK3-STAT5).90 Thus, blocking IL15 signaling seems to be promising in the search for new treatments.

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    1

    These authors contributed equally to this work.

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