MEETING REPORT

Oxidative Stress-Induced Chemokine Production

Mediates CD8 T Cell Skin Trafficking in Vitiligo
Shuli Li1, Guannan Zhu1, Yuqi Yang1, Sen Guo1, Wei Dai1, Gang Wang1, Tianwen Gao1 and Chunying Li1
The Journal of Investigative Dermatology Symposium (2015) 17, 3233; doi:10.1038/jidsymp.2015.8

In vitiligo, increased reactive oxygen

species (ROS) are believed to be
involved in disease onset, while melanocyte-specific cytotoxic CD8 T cells
infiltrating the perilesional margin
directly contribute to melanocyte loss
(van den Boorn et al., 2009; Laddha
et al., 2013; Richmond et al., 2013). A
variety of scientific evidence suggests
oxidative stressautoimmunity-mediated
melanocyte destruction as a key convergent pathway (Toosi et al., 2012; Zhang

et al., 2014). However, the exact

mechanism linking oxidative stress to
autoimmunity is largely unknown.
Chemokines have attracted significant
interest for understanding the mechanisms of leukocyte trafficking in healthy
and disease. Previous studies revealed
that a reduced functional regulatory T
cells is retained in vitiligo skin because
of significant reduced expression of
chemokine CCL22 (Klarquist et al.,
2010). Moreover, recently, Harris et al.

have provided the evidence that the

chemokine receptor CXCR3, and its
ligands, CXCL9 and CXCL10, are
critical for the skin accumulation of
cytotoxic activity of autoreactive T
cells (Harris et al., 2012; Rashighi
et al., 2014). More importantly, knocking out of the CXCR3 receptor or blocking the action of CXCL10 could prevent
and reverse depigmentation in vitiligo
(Harris et al., 2012; Rashighi et al.,
2014). All these data suggest that

Skin
Epidermis
Keratinocytes
IFN-/TNF-

1. Chemokines
released by ROS

4. Cytokines
released by T cells

3. Cytotoxic CD8+ T
mediated killing

5. Chemokines
further released by
IFN- and /or TNF-

Chemokines

CD8

Tyrosinase
gp100
MART-1

2. Melanocyte-specific
cytotoxic CD8+ T skin
migration by
chemokine and its
receptor interactions

Chemokine
Venule

6. MC destruction
and vitiligo initiation
and progression

Chemokine receptors
CLA

Dermis

Melanocytes

Chemokine receptors

CLA
CD8

Tyrosinase
gp100
MART-1

Figure 1. Reactive oxygen species (ROS) induce chemokines responsible for CD8 T cell skin trafficking and melanocyte destruction in vitiligo. (1) Oxidative
stress in vitiligo is characterized by ROS. ROS leads to chemokines production in keratinocytes. (2) In dermal venule, melanocyte-specific cytotoxic T cells
express cutaneous lymphocyte antigen (CLA) and chemokine receptors, which enable skin-specific homing by interaction with corresponding chemokines.
(3) Skin-infiltrating cytotoxic melanocyte antigen-specific T cells kill melanocytes. (4) Cytokines, such as TNF-a or IFN-g, are produced by autoreactive CD8
T cells. (5) TNF-a and/or IFN-g increased keratinocytes chemokines production, ensuring CD8 T-cell migration and further amplification of immune response.
(6) Autoimmune destruction of melanocytes in skin results in vitiligo initiation and progression.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xian, Shaanxi, China

Correspondence: Chunying Li, Department of Dermatology, Xijing Hospital, Fourth Military Medical University, No 127 of West Changle Road, Xian, Shaanxi
710032, China. E-mail: lichying@fmmu.edu.cn

32

The Journal of Investigative Dermatology Symposium (2015), Volume 17

& 2015 The Society for Investigative Dermatology

S Li et al.
Oxidative Stress-Induced Chemokine Production Mediates

understanding the mechanism of pathogenic leukocyte skin migration, as well

as the chemokine production, in
progressive vitiligo is important.
It has been well known that chemokines could be induced in response to
cytokines stimuli, like TNF-a, IFN-g, and
IL-1b, to recruit inflmmatory leukocytes
during inflammation (Bonecchi et al.,
2009). Emerging scientific studies reveal
that ROS induce chemokine production
response for the recruitment of immune
cells to particular sites (Josse et al., 2001).
Since oxidative stress is an important
trigger of vitiligo autoimmunity, we
hypothesized there is link between ROS
and the chemokine production in the
pathogenesis of vitiligo.
We tested the chemokines and their
receptors in vitiligo patients, and
explored the functional roles in recruitment of CD8 T cells, as well as the
production under oxidative stress and
inflammatory conditions. Our results
showed that oxidative stress results in
chemokines production, causing CD8
T cell skin trafficking and melanocyte
destruction in vitiligo (Figure 1, data

unpublished). Moreover, we implicate

cytokines produced by skin-infiltrating T
cells may amplificate the immune
response (Figure 1). To our knowledge,
this is previously unreported. Better
understanding of oxidative stress for
immune cell skin tafficking in vitiligo
may lead to new therapies.

Josse C, Boelaert JR, Best-Belpomme M et al.

(2001) Importance of post-transcriptional
regulation of chemokine genes by oxidative
stress. Biochem J 360:32133
Klarquist J, Denman CJ, Hernandez C et al. (2010)
Reduced skin homing by functional Treg in
vitiligo. Pigment Cell Melanoma Res 23:
27686

CONFLICT OF INTEREST

Laddha NC, Dwivedi M, Mansuri MS et al. (2013)

Vitiligo: interplay between oxidative stress
and immune system. Exp Dermatol 22:
24550

ACKNOWLEDGMENTS

Rashighi M, Agarwal P, Richmond JM et al. (2014)

CXCL10 is critical for the progression and
maintenance of depigmentation in a mouse
model of vitiligo. Sci Transl Med 6:223ra23

The authors state no conflict of interest.

We thank Professors Boquan Jin, Kun Yang

(Department of Immunology, FMMU) and Zifan
Lu (Department of Biochemistry and Molecular
Biology, FMMU) for their valuable advice and
suggestions. This work was supported by the
National Natural Science Foundation of China
(81472863 and 81172749).

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