Emerging roles of secreted phospholipase-associated lipid metabolism in allergy

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06624
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Taketomi Yoshitaka 東京大学, 大学院医学系研究科(医学部), 講師 (40365804)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 脂質メディエーター / ホスホリパーゼA2 / アレルギー / 皮膚疾患 / マスト細胞

Outline of Final Research Achievements

The production of lipid mediators is initiated by hydrolysis of membrane phospholipids by phospholipase A2 (PLA2). The present study revealed that PLA2G3 in keratinocytes plays a role in facilitating skin barrier homeostasis by mobilizing polyunsaturated fatty acid-derived lipid mediators, such as the arachidonic acid metabolites PGE2 and PGF2α. Mice lacking PLA2G3 in keratinocytes, as well as those lacking the PGE2 receptor subtype EP4 or the PGF2α receptor FP, have a defective skin barrier, which cause atopic dermatitis and eventually the atopic asthma. In addition, PLA2G3 released from immature mast cells (MCs) supplies lysophospholipid LPA as a paracrine factor, acts on the LPA receptor LPA1 on fibroblasts, which providing the precise mechanisms underlying MC-fibroblast communication leading to proper maturation of MCs. Fibroblast-secrete PLA2G12A also acts as a paracrine factor, mobilizing lysophospholipid LPE to enhance MC activation and allergic responses.

Free Research Field

脂質生物学

Academic Significance and Societal Importance of the Research Achievements

本成果は、①未解明であった皮膚中での不飽和脂肪酸の動員機序と当該脂質シグナルによる皮膚恒常性・変容の新しい制御機構、②マスト細胞微小環境を制御する未知の機能性脂質とその動員経路ならびにマスト細胞制御の動作原理を解明するものであり、将来的に、本成果を理論背景に、膜環境整備を志向した新しいアレルギーの予防治療・診断法が創出されることが期待される。