title: The role of group IIF-secreted phospholipase A2 in epidermal homeostasis and hyperplasia.
abstract: Epidermal lipids are important for skin homeostasis. However, the entire picture of the roles of lipids, particularly nonceramide lipid species, in epidermal biology still remains obscure. Here, we report that PLA2G2F, a functionally orphan-secreted phospholipase A2 expressed in the suprabasal epidermis, regulates skin homeostasis and hyperplasic disorders. Pla2g2f(-/-) mice had a fragile stratum corneum and were strikingly protected from psoriasis, contact dermatitis, and skin cancer. Conversely, Pla2g2f-overexpressing transgenic mice displayed psoriasis-like epidermal hyperplasia. Primary keratinocytes from Pla2g2f(-) (/-) mice showed defective differentiation and activation. PLA2G2F was induced by calcium or IL-22 in keratinocytes and preferentially hydrolyzed ethanolamine plasmalogen-bearing docosahexaenoic acid secreted from keratinocytes to give rise to unique bioactive lipids (i.e., protectin D1 and 9S-hydroxyoctadecadienoic acid) that were distinct from canonical arachidonate metabolites (prostaglandins and leukotrienes). Ethanolamine lysoplasmalogen, a PLA2G2F-derived marker product, rescued defective activation of Pla2g2f(-/-) keratinocytes both in vitro and in vivo. Our results highlight PLA2G2F as a previously unrecognized regulator of skin pathophysiology and point to this enzyme as a novel drug target for epidermal-hyperplasic diseases.
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Miki
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan School of Science and Engineering, Tokyo Denki University, Saitama 350-0394, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Sato
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Taketomi
authors.affiliation: Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Nishito
authors.affiliation: Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Choji
authors.initials: C
authors.lastname: Taya
authors.affiliation: School of Science and Engineering, Tokyo Denki University, Saitama 350-0394, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Muramatsu
authors.affiliation: Laboratory for Metabolomics, Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Research Center for Biosignal, Akita University, Akita 010-8543, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: College of Bioscience and Biotechnology, Chubu University, Aichi 487-8501, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.affiliation: Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8677, Japan.
authors.forename: Naotomo
authors.initials: N
authors.lastname: Kambe
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275, Centre National de la Recherche Scientifique et Université de Nice-Sophia-Antipolis, 06560 Valbonne, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.affiliation: Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA 98195.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan CREST, Japan Agency for Medical Research and Development (AMED) and Japan Science and Technology Agency (JST), Tokyo 100-0004, Japan murakami-mk@igakuken.or.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003877:Dermatitis, Contact / Q000473:pathology; D004817:Epidermis / Q000473:pathology*; D054501:Group II Phospholipases A2 / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D006965:Hyperplasia; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011565:Psoriasis / Q000473:pathology; D012878:Skin Neoplasms / Q000209:etiology
chemical_list: D054501:Group II Phospholipases A2; C516297:Pla2g2f protein, mouse