Yamamoto Kei, Miki Yoshimi, Sato Mariko, Taketomi Yoshitaka, Nishito Yasumasa, Taya Choji, Muramatsu Kazuaki, Ikeda Kazutaka, Nakanishi Hiroki, Taguchi Ryo, Kambe Naotomo, Kabashima Kenji, Lambeau Gérard, Gelb Michael H, Murakami Makoto
Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
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.
J Exp Med. 2015 Oct 19;212(11):1901-19. doi: 10.1084/jem.20141904. Epub 2015 Oct 5.
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.
表皮脂质对皮肤稳态至关重要。然而，脂质尤其是非神经酰胺脂质种类在表皮生物学中的作用全貌仍不清楚。在此，我们报道PLA2G2F，一种在上皮上层表皮中表达的功能未知的分泌型磷脂酶A2，可调节皮肤稳态和增生性疾病。Pla2g2f(-/-)小鼠角质层脆弱，对银屑病、接触性皮炎和皮肤癌具有显著的抵抗力。相反，过表达Pla2g2f的转基因小鼠表现出银屑病样的表皮增生。来自Pla2g2f(-/-)小鼠的原代角质形成细胞显示出分化和激活缺陷。PLA2G2F在角质形成细胞中由钙或IL-22诱导，并优先水解角质形成细胞分泌的含二十二碳六烯酸的乙醇胺缩醛磷脂，产生独特的生物活性脂质（即保护素D1和9S-羟基十八碳二烯酸），这些脂质不同于经典的花生四烯酸代谢产物（前列腺素和白三烯）。乙醇胺溶血缩醛磷脂，一种PLA2G2F衍生的标记产物，在体外和体内均挽救了Pla2g2f(-/-)角质形成细胞的激活缺陷。我们的结果突出了PLA2G2F作为一种先前未被认识的皮肤病理生理学调节因子，并指出该酶是表皮增生性疾病的新型药物靶点。
