title: Retinoid-X-receptors (α/β) in melanocytes modulate innate immune responses and differentially regulate cell survival following UV irradiation.
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.
authors.affiliation: Department 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.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Coleman
authors.affiliation: Department 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.
authors.forename: Gloria
authors.initials: G
authors.lastname: Garcia
authors.affiliation: Department 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.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hyter
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Hyo Sang
authors.initials: HS
authors.lastname: Jang
authors.affiliation: Department 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.
authors.forename: Sharmeen
authors.initials: S
authors.lastname: Chagani
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Liang
authors.affiliation: Developmental Genetics of Melanocytes, Institut Curie, Centre de Recherche, Orsay, France; CNRS UMR3347, Orsay, France; INSERM U1021, Orsay, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
authors.affiliation: Department 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.
authors.forename: Gitali
authors.initials: G
authors.lastname: Ganguli-Indra
authors.affiliation: Department 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.
authors.forename: Arup K
authors.initials: AK
authors.lastname: Indra
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000528:radiation effects*; D007113:Immunity, Innate / Q000502:physiology*; D008544:Melanocytes / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000502:physiology*; D049230:Retinoid X Receptor beta / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays
chemical_list: D047490:Retinoid X Receptor alpha; D049230:Retinoid X Receptor beta