Melanocyte Regeneration in Vitiligo Requires WNT beneath their Wings.

Melanocytes in patients with vitiligo possess intrinsic abnormalities that contribute to its pathogenesis. Regazzetti et al. report that CXCL10 expression reflects subtle inflammation in normal-appearing skin but not in stable depigmented lesions, supporting the hypothesis that melanocytes themselves initiate autoimmune inflammation prior to clinically evident disease. In addition, they find that oxidative stress in melanocytes impairs WNT signaling and that targeting this pathway induces melanoblast differentiation. Thus, activating the WNT pathway may serve as an adjunctive strategy to support repigmentation in patients with vitiligo.

In this issue, Regazzetti, et al. report that WNT signaling is impaired in lesional and non-lesional skin of patients with vitiligo. Because WNT signaling promotes the differentiation of melanocyte precursors in skin (Yamada ), impaired signaling may affect the ability of melanocytes to proliferate and differentiate into functional melanocytes during therapeutic repigmentation. Current treatments for vitiligo include topical anti-inflammatory compounds, such as corticosteroids and calcineurin inhibitors, which inhibit autoimmune responses, as well as narrow-band ultraviolet radiation B (nbUVB) (Ezzedine ), which likely inhibit autoimmunity and promotes melanocyte regeneration. Repigmentation in vitiligo begins within 6–12 weeks after initiating treatment, and it frequently occurs in a perifollicular pattern (Figure). A recent study has reported that nbUVB treatment of vitiligo is associated with proliferation, migration, and differentiation of melanocytes in the hair follicles and epidermis of lesional skin (Goldstein ). The current study suggests that impaired WNT signaling in vitiligo slows this process and that promoting this pathway may improve repigmentation by enhancing melanocyte differentiation.

Figure

Perifollicular repigmentation in a vitiligo patient during nbUVB phototherapy.

It is now well-established that melanocytes in vitiligo have increased oxidative stress, reflected by elevated levels of reactive oxidative species (ROS) in cultured cells in vitro and within the epidermis in vivo (Ezzedine ; Glassman, 2011). This may play an important role in its pathogenesis, possibly by initiating inflammation and autoimmunity in the skin (Richmond ). However the current study now indicates that oxidative stress may also be partly responsible for impaired WNT signaling, as melanocytes exposed to oxidative stress in vitro decreased the expression of WNT family members. Thus, oxidative stress may both promote autoimmune inflammation and impair melanocyte regeneration during treatment. The authors reasoned that if WNT signaling were important for melanocyte differentiation but impaired in patients with vitiligo, then pharmacological activators of this pathway might help promote melanocyte differentiation in the skin. Indeed, the authors demonstrated that members of the WNT signaling pathway are induced in the skin by a chemical WNT agonist and two antagonists of GSK-β (a negative regulator of the pathway) and that this treatment promotes the differentiation of melanoblast precursors in skin affected by vitiligo. They suggest that stimulating WNT signaling may serve as an adjunct to current therapies. It is possible that WNT activators could synergize with anti-inflammatory treatments to simultaneously shut down autoimmunity and promote melanocyte regeneration.

We previously reported transcriptional differences in the lesional skin of vitiligo patients compared to healthy control skin, but focused on lesions with active inflammation in order to reveal the cytokine and chemokine patterns responsible for driving autoimmunity. This approach revealed an IFN-γ-specific signature, and CXCL10, an IFN-γ-induced chemokine, was the most highly expressed gene in lesional skin. We further determined that CXCL10 was elevated in a mouse model of vitiligo that we developed, and that it was required functionally for both the progression of vitiligo as well as the maintenance of disease, as neutralizing CXCL10 both prevented depigmentation as well as reversing established disease (Rashighi ). The current study by Regazzetti et al. also found that CXCL10 is elevated in perilesional skin in vitiligo, although the magnitude of expression was lower than in our study. This is likely due to the fact that we profiled only lesional skin with a significant mononuclear infiltrate by histology, while the present study profiled perilesional skin indiscriminately, which would usually include sites with very mild inflammation.

But the current study went further, analyzing also stably depigmented and normally pigmented skin from vitiligo, and it compared these results with normal, control skin, as well. This revealed that the expression of CXCL10 is mildly elevated also in nonlesional, normally pigmented skin in vitiligo, when compared to healthy control skin, which suggests that subtle inflammation is present even before the appearance of clinically evident lesions. This may indicate a predisposition in all of the skin of patients to develop vitiligo, and this may reflect the ability of tolerance mechanisms to keep low-level inflammation “in check”, thereby preventing new lesions from appearing. Previous studies have reported an important role for T regulatory cells in controlling the spread of depigmentation in mouse models of vitiligo (Chatterjee ; Gregg ), which may be a key mechanism that controls further depigmentation. Importantly, in contrast to normally pigmented skin, completely depigmented skin from patients with vitiligo (old, inactive lesions) did not have elevated CXCL10, suggesting that the presence of melanocytes was required to fuel the low-level inflammation. Melanocytes in vitiligo are not simply targets of autoimmunity; rather, they contain intrinsic defects that help to initiate the autoimmune destruction that is observed in vitiligo (Passeron and Ortonne, 2012; Richmond ). Future studies may reveal how “abnormal” melanocytes promote autoimmunity in vitiligo, and specifically how CXCL10 is initially induced in disease.

The study by Regazzetti, et al. confirms our findings that CXCL10 is expressed within active lesional skin in vitiligo (Rashighi ), and, further, it suggests that subtle inflammation is ongoing in even the normally pigmented skin. In addition, this study connects oxidative stress in melanocytes to the WNT signaling pathway, revealing that intrinsic defects in melanocytes from such patients likely include impaired WNT signaling. Finally, the authors hypothesize that pharmacological activation of the pathway could help to promote melanocyte differentiation and repigmentation during treatment, serving as the “WNT beneath the wings” of regenerating melanocytes, which must go through a series of steps, beginning with differentiation of melanocyte precursors in the hair follicles or other niches of the skin and then progressing through proliferation, migration, and further differentiation into functional melanocytes. The study used an innovative new ex vivo vitiligo skin culture model to demonstrate that WNT activators begin this process by differentiating melanoblasts but, due to the limited time the cultures could be maintained ex vivo, the authors were unable to determine whether this would progress to promote fully functional melanocytes. It is not clear what role WNT signaling plays in events downstream of melanocyte differentiation, and future studies will hopefully to assess this in order to translate these results into new treatments.