Journal
PLOS GENETICS
Volume 10, Issue 5, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004321
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Funding
- National Institute of Environmental Health Sciences, National Institutes of Health [P30 ES00210]
- National Cancer Institute [P30CA069533]
- National Institute of Environmental Health Sciences of the National Institutes of Health [ES016629-01A1, ES00210]
- National Cancer Institute of the National Institutes of Health [T32CA106195]
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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 a (RXR alpha) is lost during melanoma progression in humans. Here, we observed that in mice with melanocyte-specific ablation of RXRa and RXR beta, melanocytes attract fewer IFN-gamma secreting immune cells than in wild-type mice following acute UVR exposure, via altered expression of several chemoattractive and chemorepulsive chemokines/cytokines. Reduced IFN-gamma in the microenvironment alters UVR-induced apoptosis, and due to this, the survival of surrounding dermal fibroblasts is significantly decreased in mice lacking RXR alpha/beta. Interestingly, post-UVR survival of the melanocytes themselves is enhanced in the absence of RXRa/b. Loss of RXRs alpha/beta 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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