Elucidation of the molecular mechanism and development of therapeutic strategies for the sphingolipid-mediated pregnancy loss

2015 Fiscal Year Final Research Report

• Project/Area Number: 24591600
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Embryonic/Neonatal medicine
• Research Institution: Kyoto University
• Principal Investigator: Mizugishi Kiyomi 京都大学, 医学(系)研究科(研究院), 研究員 (70518448)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Keywords: スフィンゴ脂質 / 妊娠 / 不育症 / 自然免疫 / ケモカイン

Outline of Final Research Achievements

Perturbation of the sphingolipid pathway by disruption of the sphingosine kinase gene (Sphk) during pregnancy caused unusually high expression of neutrophil chemoattractants, CXCL1 and CXCL2, in the decidua, leading to a massive infiltration of neutrophils into the fetomaternal interface with enhanced oxidative damage, resulting in early fetal death. The blockage of neutrophil influx protected Sphk-deficient mice against pregnancy loss. Notably, a similar result was obtained in human decidual cells, in which Sphk deficiency dramatically increased the secretion of CXCL1 and IL-8. In conclusion, our findings suggest that the sphingolipid metabolic pathway plays a critical role in fetomaternal tolerance by regulating innate immunity at the fetomaternal interface both in mice and humans, and it could provide novel insight into the development of therapeutic strategies to treat idiopathic pregnancy loss in humans.

Free Research Field

スフィンゴ脂質