Abstract
Repigmentation of the skin in patients with vitiligo represents an intricate process in which the depigmented epidermis is replenished by functional melanocytes (MCs) that migrate from undamaged hair follicles and/or surrounding areas. We characterized whether MCs release a secreted form of Pmel17 (sPmel17) protein after exposure to UVB, thereby weakening the cell-cell adhesions of keratinocytes (KCs), which provides MCs the opportunity to migrate to areas devoid of MCs. At first, we examined the interactions of sPmel17 and FHL2 (four-and-a-half LIM domain protein 2) in KCs treated with the conditioned media (CM) from MCs exposed to UVB. The results showed that both the protein and mRNA levels of FHL2 were significantly upregulated in KCs treated with sPmel17-enriched CM from UVB-exposed MCs. We also found that there are physical interactions between sPmel17 and FHL2 as analyzed by reciprocal coimmunoprecipitation assays and double immunofluorescence staining. The CM from UVB-exposed MCs signaled KCs to remodel the actin cytoskeleton and reduce E-cadherin expression. However, the CM from UVB-exposed and Pmel17-silenced or from UVB-unexposed MCs failed to do this. To further determine the in situ distributions of sPmel17, FHL2, and E-cadherin, we examined the expression profiles of those proteins in the skin from healthy subjects and from depigmented or repigmented vitiligo using immunofluorescence and immunohistochemical staining. The results showed that the expression of sPmel17 was positively correlated with FHL2 but not to E-cadherin. The colocalization of FHL2 and sPmel17 was also observed in UVB-exposed mouse tail skin. Together, the upregulation of FHL2 in KCs requires stimulation by sPmel17 secreted from MCs and activation of the sPmel17-FHL2-E-cadherin axis offers a potential therapeutic target to expedite the repigmentation process in patients with vitiligo.
Highlights
Vitiligo is a chronic, acquired autoimmune disorder characterized by circumscribed depigmented macules in the skin that result from the loss of pigment-producing cells known as melanocytes (MCs) [1, 2]
We examined the mRNA expression levels of melanogenesisassociated genes (MITF, TYR, TYRP1, DCT, and Pmel17) and the migration-related gene MCAM in MCs exposed or unexposed to 30 mJ/cm2 UVB. Quantitative Real-Time RT-PCR (qRT-PCR) analysis showed that exposure to UVB significantly upregulates the expression of all melanogenesis-associated genes and MCAM at the transcriptional level (Figure 1(a))
The results showed that immunoreactivities with anti-secreted form of Pmel17 (sPmel17) and anti-four and a half LIM domains 2 (FHL2) antibodies almost completely disappeared in the vitiliginous lesions; the restoration of immunostaining using those same antibodies was found in the repigmented skins from the same vitiligo patients (Figure 6(a))
Summary
Vitiligo is a chronic, acquired autoimmune disorder characterized by circumscribed depigmented macules in the skin that result from the loss of pigment-producing cells known as melanocytes (MCs) [1, 2]. Phototherapies using narrowband ultraviolet B (NB-UVB), a 308 nm excimer laser, or monochromatic excimer light have been clinically proven to be effective in the treatment of vitiligo [4]. The responsiveness to such phototherapies varies greatly in different patients with vitiligo. A recent study indicated that almost 25% of vitiligo patients have a poor response to NB-UVB phototherapy even after 12 months of treatment [5]. The unsatisfactory benefit of current phototherapy regimens prompted us to examine the mechanism behind UVB-induced repigmentation in an attempt to identify new therapeutic targets to improve the treatment outcome for vitiligo patients
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