Sexually Dimorphic Inflammatory Responses Key to Understanding Vitiligo, Study Finds

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While treatments targeting T cells show promise, achieving durable repigmentation in vitiligo remains a challenge, according to authors of a recent study. In the study, published in Nature Communications, researchers explored the mechanisms of melanocyte migration in a mice model.¹

Several previous studies, they noted, have uncovered how melanocyte stem cells (McSCs) become active and change in different situations. They involve molecules like Mitf, the Tfap2 family, Wnt signaling from keratinocytes, Bmp signaling, and the Mc1R-cAMP pathway.²

The study focused on McSCs residing in hair follicles as a potential source for repigmentation. By utilizing a murine UVB irradiation model mimicking phototherapy for vitiligo, researchers identified promotors of McSC proliferation and epidermal repopulation post-UVB exposure. As a result, they found that cyclooxygenase signaling or prostaglandin E2 supplementation enhances this process.

Through imaging and genetic analyses, researchers unveiled sex-based differences in McSC migration, with male mice exhibiting heightened migration rates due to increased skin inflammation. This finding, they wrote, points to the role of innate immune cells in the facilitation of melanocyte migration.

Using an inflammatory agent, imiquimod, in conjunction with UVB irradiation, researchers observed a significant increase in McSC migration rates compared to controls. However, imiquimod alone did not induce McSC migration, indicating that UVB irradiation is necessary for this process.

Single-cell mRNA sequencing revealed a transition in macrophage populations after UVB irradiation, including distinct pro-inflammatory macrophage subtypes. These macrophages expressed higher levels of inflammatory cytokines and chemokines, contributing to the recruitment of immune cells such as neutrophils. Depletion of macrophages resulted in decreased McSC migration, researchers wrote.

Further analysis uncovered enhanced prostaglandin signaling, particularly in male mice, following UVB irradiation. In males, an increased expression of cyclooxygenases and prostaglandin synthesis factors positively correlated with heightened inflammation and McSC migration rates. Additionally, global depletion of Cox-2, a key enzyme in prostaglandin synthesis, led to a reduction in McSC migration.

"Here, we demonstrated the pro-inflammatory role of macrophages and its impact on McSC epidermal migration following UVB irradiation. Inflammation is a well-studied biological process that involves a broad range of cells and molecules, including but not limited to macrophages, neutrophils, dendritic cells, T cells, keratinocytes, and fibroblasts," wrote study authors. "Future investigations may shed light on the roles of other cell types and pathways in regulating the inflammatory response in the skin after UVB irradiation. It should be noted that McSC migration was not induced independently by imiquimod, dmPGE2 or Cox-2 overexpression in the absence of UVB irradiation, suggesting that other cell types and signaling pathways are involved in McSC migration, in addition to inflammation, such as Kitl expression in keratinocytes under UVB expression."

By combining pro-inflammation modalities with anti-T cell agents, researchers aim to improve the efficacy of current treatments and offer new avenues for vitiligo management, eventually translating this approach in patients with vitiligo and cutaneous depigmentation.

"Taken together, this work demonstrates the translational feasibility of combining pro-inflammation modalities (to promote enhanced melanocyte recruitment) with anti-T cell agents to generate a more favorable outcome compared to phototherapy and immunosuppressant-only treatments used currently," according to An et al.

References

1. An L, Kim D, Donahue LR, et al. Sexual dimorphism in melanocyte stem cell behavior reveals combinational therapeutic strategies for cutaneous repigmentation. Nat Commun. (2024). Accessed April 1, 2024. https://doi.org/10.1038/s41467-024-45034-3
2. Levy C, Khaled M, Fisher DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol. Med. (2006). Accessed April 1, 2024.