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.