title: Keratinocyte-specific deletion of the receptor RAGE modulates the kinetics of skin inflammation in vivo.
abstract: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor causally related to the pathogenesis of acute and chronic inflammation. In a mouse model of inflammation-driven skin carcinogenesis, RAGE deletion conferred protection from the development of skin tumors due to a severely impaired cutaneous inflammation. Although the impact of RAGE expression in immune cells was shown to be essential for the maintenance of a cutaneous inflammatory reaction, the role of RAGE in keratinocytes remained unsolved. Using mice harboring a keratinocyte-specific deletion of RAGE, we analyzed its role in the regulation of an acute inflammatory response that was induced by topical treatment of the back skin with the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We show that RAGE expression in cutaneous keratinocytes modulates the strength and kinetics of acute inflammation and supports the maintenance of epidermal keratinocyte activation. To address the underlying molecular mechanism, we isolated interfollicular epidermis by laser microdissection for gene expression analysis, and identified RAGE as a regulator in the temporal control of TPA-induced epidermal tumor necrosis factor alpha transcript levels. In summary, our data demonstrate that RAGE expression in keratinocytes is critically involved in the perpetuation of acute inflammation and support the central role of RAGE in paracrine communication between keratinocytes and stromal immune cells.
authors.affiliation: Division Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Leibold
authors.affiliation: Division Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Riehl
authors.affiliation: Junior Research Group Immune Tolerance, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Hettinger
authors.affiliation: Department of Immunology, Eberhard-Karls University, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Durben
authors.affiliation: Junior Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany; Experimental Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital, Heidelberg, Germany. Electronic address: jochen.hess@med.uni-heidelberg.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
authors.affiliation: Division Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D003872:Dermatitis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D005260:Female; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D019899:Paracrine Communication / Q000276:immunology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D002273:Carcinogens; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate