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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Authors | Daniel J Coleman, Gloria Garcia, Stephen Hyter, Hyo Sang Jang, Sharmeen Chagani, Xiaobo Liang, Lionel Larue, Gitali Ganguli-Indra, Arup K Indra |
Journal | PLoS genetics
(PLoS Genet)
Vol. 10
Issue 5
Pg. e1004321
(May 2014)
ISSN: 1553-7404 [Electronic] United States |
PMID | 24810760
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Retinoid X Receptor alpha
- Retinoid X Receptor beta
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Topics |
- Animals
- Cell Cycle
(radiation effects)
- Immunity, Innate
(physiology)
- Melanocytes
(physiology, radiation effects)
- Mice
- Mice, Transgenic
- Retinoid X Receptor alpha
(genetics, physiology)
- Retinoid X Receptor beta
(genetics, physiology)
- Ultraviolet Rays
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