摘要:
Post-inflammatory hyperpigmentation (PIH) is a common skin disorder characterized by brown or black macules. It can be categorized as transient, typically resolving within 6–12 months, or permanent, persisting for years. While the pathogenesis of PIH is commonly linked to localized melanocyte overactivation, the precise cellular and molecular basis for this dysregulation, as well as its physiological significance, remains poorly defined. Using an acetic acid-induced zebrafish model, we identify melanocyte migration as a critical driver of hyperpigmentation. This process is independent of immune cells but driven by fibroblasts, which secrete Cxcl12a to recruit melanocytes via the Cxcl12a–Cxcr4a axis. Fibroblast ablation irreversibly disrupts melanocyte patterning, indicating that aberrant fibroblast activity dictates the permanence of PIH. The recruited melanocytes form a dual protective barrier against both UV-induced DNA damage and microbial intrusion. The translational relevance of this mechanism is underscored by upregulated CXCL12 expression in fibroblasts from human PIH-related conditions such as keloids, acne, and atopic dermatitis. Therapeutically, the FDA-approved CXCR4 antagonist AMD3100 (Plerixafor) effectively prevents and treats PIH in our model. Our findings elucidate a fibroblast-mediated mechanism of melanocyte recruitment in PIH, uncover previously unappreciated barrier functions of melanocytes in skin repair, and propose a promising repurposed treatment strategy.
Abstract:
Post-inflammatory hyperpigmentation (PIH) is a common skin disorder characterized by brown or black macules. It can be categorized as transient, typically resolving within 6–12 months, or permanent, persisting for years. While the pathogenesis of PIH is commonly linked to localized melanocyte overactivation, the precise cellular and molecular basis for this dysregulation, as well as its physiological significance, remains poorly defined. Using an acetic acid-induced zebrafish model, we identify melanocyte migration as a critical driver of hyperpigmentation. This process is independent of immune cells but driven by fibroblasts, which secrete Cxcl12a to recruit melanocytes via the Cxcl12a–Cxcr4a axis. Fibroblast ablation irreversibly disrupts melanocyte patterning, indicating that aberrant fibroblast activity dictates the permanence of PIH. The recruited melanocytes form a dual protective barrier against both UV-induced DNA damage and microbial intrusion. The translational relevance of this mechanism is underscored by upregulated CXCL12 expression in fibroblasts from human PIH-related conditions such as keloids, acne, and atopic dermatitis. Therapeutically, the FDA-approved CXCR4 antagonist AMD3100 (Plerixafor) effectively prevents and treats PIH in our model. Our findings elucidate a fibroblast-mediated mechanism of melanocyte recruitment in PIH, uncover previously unappreciated barrier functions of melanocytes in skin repair, and propose a promising repurposed treatment strategy.
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