CXCL10 Is Critical for the Progression and Maintenance of Depigmentation in a Mouse Model of Vitiligo

Abstract

Vitiligo is an autoimmune disease of the skin that results in disfiguring white spots. There are no FDA-approved treatments for vitiligo, and most off-label treatments yield unsatisfactory results. Vitiligo patients have increased numbers of autoreactive, melanocyte-specific CD8+ T cells in the skin and blood, which are directly responsible for melanocyte destruction. Here we report that gene expression in lesional skin from vitiligo patients reveals an IFN-γ-specific signature, including the chemokine CXCL10. CXCL10 is elevated in both vitiligo patient skin and serum and CXCR3, its receptor, is expressed on pathogenic T cells. To address the function of CXCL10 in vitiligo, we employed a mouse model of disease that also exhibits an IFN-γ-specific gene signature, expression of CXCL10 in the skin, and upregulation of CXCR3 on antigen-specific T cells. Mice that receive Cxcr3−/− T cells develop minimal depigmentation, as do mice lacking Cxcl10 or treated with CXCL10 neutralizing antibody. CXCL9 promotes autoreactive T cell global recruitment to the skin but not effector function while, in contrast, CXCL10 is required for effector function and localization within the skin. Surprisingly, CXCL10 neutralization in mice with established, widespread depigmentation induces reversal of disease, evidenced by repigmentation. These data identify a critical role for CXCL10 in both the progression and maintenance of vitiligo, and thereby support inhibiting CXCL10 as a targeted treatment strategy.

The Regulation of Immunological Processes by Peripheral Neurons in Homeostasis and Disease

“…The skin-resident immune system also provides a diverse repertoire of cell subsets with dedicated roles in host defense [3, 178]. Autoinflammatory and allergic diseases of the skin, such as atopic dermatitis and psoriasis, are characterized by symptoms of discomfort, pain and itch which are transmitted via dedicated nociceptive or pruriceptive neurons, yet this is not the case in other cutaneous autoimmune diseases, such as vitiligo which is usually painless [31, 156, 179, 180]. …”

Oxidative Stress-Induced Chemokine Production Mediates CD8+ T Cell Skin Trafficking in Vitiligo

“…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 (1) Oxidative stress in vitiligo is characterized by ROS.…”

“…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).…”

Epigallocatechin-3-gallate (EGCG) Suppresses the Trafficking of Lymphocytes to Epidermal Melanocytes <i>via</i> Inhibition of JAK2: Its Implication for Vitiligo Treatment

“…2,21,23,24) To further address the effects of EGCG on the expression of chemoattractants, we measured the expression levels of ICAM-1 and CXCL10, as well as monocyte chemotactic protein (MCP)-1 which is also implicated in the pathogenesis of certain autoimmune diseases. 25,26) The results showed that IFN-γ stimulation significantly increased the mRNA expression and protein secretion of ICAM-1, CXCL10, and MCP-1.…”