a. Biomedical Research Institute, Shenzhen Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong 518036, China;
b. Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China;
c. Division of Life Science, the Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China;
d. Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China;
e. Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China
Funds:
We are grateful to Dr. Bo Yan (Shanghai Public Health Clinical Center, Fudan University, China) for sharing M. marinum bacteria
UAS:NTR-mCherry) transgenic lines. This work was supported by the National Natural Science Foundation of China (32300696), Shenzhen Natural Science Foundation in Basic Research Fund (JCYJ20250604190941056), National Natural Science Foundation of China (32430030), National Key Research and Development Program of China (2023YFA1800100), Shenzhen Medical Research Fund (B2302034), and Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation (“Climbing Program” Special Funds, pdjh2025c21701).
to Dr. Qiang Wang (South China University of Technology, China) for generously providing the unpublished cxcl12a and cxcr4b mutant zebrafish lines, and to Dr. Huang Peng (Alberta Children's Hospital Research Institute, University of Calgary) for sharing the TgBAC(col1a2:Gal4
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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