Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Oxid Med Cell Longev. 2022 Feb 10;2022:1856830. doi: 10.1155/2022/1856830. eCollection 2022.
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.
白癜风患者的皮肤复色代表了一个复杂的过程，在此过程中，失色的表皮被功能性黑素细胞（MCs）所补充，这些细胞从未受损的毛囊和/或周围区域迁移而来。我们的研究目的是鉴定 MCs 在暴露于 UVB 后是否会释放一种分泌型 Pmel17（sPmel17）蛋白，从而削弱角质细胞（KCs）的细胞间黏附力，使 MCs 有机会迁移到缺乏 MCs 的区域。首先，我们在接受暴露于 UVB 的 MC 条件培养基（CM）处理的 KCs 中，研究了 sPmel17 与 FHL2（four-and-a-half LIM domain protein 2）的相互作用。结果显示，在接受富含 sPmel17 的 UVB 暴露 MC CM 处理的 KCs 中，FHL2 的蛋白和 mRNA 水平均显著上调。我们还发现，通过相互免疫沉淀分析和双免疫荧光染色分析，sPmel17 与 FHL2 之间存在物理相互作用。来自 UVB 暴露 MC 的 CM 信号使 KCs 重塑肌动蛋白细胞骨架并降低 E-钙黏蛋白的表达。然而，来自 UVB 暴露和 Pmel17 沉默或未暴露于 UVB 的 MC 的 CM 则无法做到这一点。为了进一步确定 sPmel17、FHL2 和 E-钙黏蛋白的原位分布，我们使用免疫荧光和免疫组织化学染色，在健康受试者和脱色素或复色白癜风患者的皮肤中检测这些蛋白的表达谱。结果表明，sPmel17 的表达与 FHL2 呈正相关，而与 E-钙黏蛋白无关。在 UVB 暴露的小鼠尾部皮肤中也观察到 FHL2 和 sPmel17 的共定位。综上所述，KC 中 FHL2 的上调需要来自 MC 的分泌型 sPmel17 的刺激，激活 sPmel17-FHL2-E-钙黏蛋白轴为加速白癜风患者的复色过程提供了一个潜在的治疗靶点。
