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PLoS Genet. 2014 May 8;10(5):e1004321. doi: 10.1371/journal.pgen.1004321. eCollection 2014.

Retinoid-X-receptors (α/β) in melanocytes modulate innate immune responses and differentially regulate cell survival following UV irradiation.

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  • 1Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America; Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon, United States of America.
  • 2Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America.
  • 3Developmental Genetics of Melanocytes, Institut Curie, Centre de Recherche, Orsay, France; CNRS UMR3347, Orsay, France; INSERM U1021, Orsay, France.
  • 4Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America; Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon, United States of America; Dermatology Research Division, Oregon Health and Science University, Portland, Oregon, United States of America.

Abstract

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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