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Retinoid-X-Receptors (α/β) in Melanocytes Modulate Innate Immune Responses and Differentially Regulate Cell Survival following UV Irradiation

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https://ir.library.oregonstate.edu/concern/articles/h128ng487

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  • Understanding the molecular mechanisms of ultraviolet (UV) induced melanoma formation is becoming crucial with more reported cases each year. Expression of type II nuclear receptor Retinoid-X-Receptor α (RXRα) is lost during melanoma progression in humans. Here, we observed that in mice with melanocyte-specific ablation of RXRα and RXRβ, melanocytes attract fewer IFN-γ secreting immune cells than in wild-type mice following acute UVR exposure, via altered expression of several chemoattractive and chemorepulsive chemokines/cytokines. Reduced IFN-γ in the microenvironment alters UVR-induced apoptosis, and due to this, the survival of surrounding dermal fibroblasts is significantly decreased in mice lacking RXRα/β. Interestingly, post-UVR survival of the melanocytes themselves is enhanced in the absence of RXRα/β. Loss of RXRs α/β specifically in the melanocytes results in an endogenous shift in homeostasis of pro- and anti-apoptotic genes in these cells and enhances their survival compared to the wild type melanocytes. Therefore, RXRs modulate post-UVR survival of dermal fibroblasts in a “non-cell autonomous” manner, underscoring their role in immune surveillance, while independently mediating post-UVR melanocyte survival in a “cell autonomous” manner. Our results emphasize a novel immunomodulatory role of melanocytes in controlling survival of neighboring cell types besides controlling their own, and identifies RXRs as potential targets for therapy against UV induced melanoma.
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  • Coleman DJ, Garcia G, Hyter S, Jang HS, Chagani S, et al. (2014) Retinoid-X-Receptors (α/β) in Melanocytes Modulate Innate Immune Responses and Differentially Regulate Cell Survival following UV Irradiation. PLoS Genetics 10(5): e1004321. doi:10.1371/journal.pgen.1004321
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  • 10
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  • 5
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  • We are grateful for services provided by the Cell and Tissue Analysis Facilities and Services Core of the EHSC at OSU, grant number P30 ES00210, National Institute of Environmental Health Sciences, National Institutes of Health; specifically C. Samuel Bradford for help with flow cytometry. We also thank the OHSU Knight Cancer Institute, funded by the National Cancer Institute, P30CA069533. Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under award numbers ES016629-01A1 and ES00210, as well as the National Cancer Institute of the National Institutes of Health under award number T32CA106195.
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