Novel mechanisms of pregnancy complications resulting in the innate immune response in the syncytiotrophoblast induced by double-stranded RNA

• Project/Area Number: 17K18404
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology; Embryonic/Neonatal medicine
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Motomura Kenichiro 国立研究開発法人国立成育医療研究センター, 免疫アレルギー・感染研究部, 共同研究員 (00724329)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 合胞体栄養膜細胞 / 妊娠合併症 / パターン認識受容体 / 二本鎖RNA / 胎盤 / 合胞体栄養栄養膜細胞 / Apoptosis / 自然免疫系受容体

Outline of Final Research Achievements

We analyzed the expression and function of double-stranded RNA receptors on human syncytiotrophoblast. The syncytiotrophoblast play a central role in the placental functions. Using primary human term placenta-derived syncytiotrophoblast culture model, we showed that double-stranded RNA (dsRNA) receptors (TLR3, MDA5, RIG-I) are predominantly expressed on the syncytiotrophoblast, and the stimulations via these receptors using a dsRNA analogue, poly:IC induced 1) the production of inflammatory cytokines and chemokines, 2) the production of anti-viral molecules, and 3) caspase 3/7-dependent apoptosis. Moreover, using a pregnant mice model, we demonstrated that intravenous administration of dsRNA induced fetal growth restriction, and this process was turned out to be via TLR 3. These results suggest the link between dsRNA receptors and pregnancy complications and the possibility of double stranded RNA receptors as a novel biomarker or a therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

炎症が関与する妊娠合併症は未だに原因が明らかになっていないものが多く、これが根治療法の開発を困難にしている。本研究は合胞体栄養膜細胞に発現する二本鎖RNA受容体に着目し、これらを介した刺激が誘導する胎盤での免疫反応の一端を明らかにした。今後臨床検体を用いた検討を組み合わせることで、胎盤障害の新たなメカニズム・バイオマーカーが明らかとなる可能性が示唆された。

Research Products

• [Journal Article] A Rho-associated coiled-coil containing kinases (ROCK) inhibitor, Y-27632, enhances adhesion, viability and differentiation of human term placenta-derived trophoblasts in vitro (2017)
  • Author(s): Kenichiro Motomura, Naoko Okada, Hideaki Morita, Mariko Hara, Masato Tamari, Keisuke Orimo, Go Matsuda, Ken-Ichi Imadome, Akio Matsuda, Takeshi Nagamatsu, Mikiya Fujieda, Haruhiko Sago, Hirohisa Saito, and Kenji Matsumoto
  • Journal Title: PLOS ONE Volume: in press Issue: 5 Pages: e0177994-e0177994
  • DOI: 10.1371/journal.pone.0177994
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] サイトカインネットワーク (2017)
  • Author(s): 本村健一郎 松本健治
  • Journal Title: 周産期医学 Volume: 47 Pages: 1521-1526
• [Presentation] Double-stranded RNA regulates BCL2 family molecules and induces apoptosis in human cultured syncytiotrophoblasts via toll-like receptor 3. A possible mechanism for pregnancy complications? (2017)
  • Author(s): Kenichiro Motomura, Haruhiko Sago
  • Organizer: 日本産科婦人科学会学術講演会
• [Presentation] Differentiated cytotrophoblasts induce anti-viral responses through receptors for double-stranded RNA (2017)
  • Author(s): Kenichiro Motomura, Naoko Okada, Hideaki Morita, Akio Matsuda, Haruhiko Sago, Hirohisa Saito and Kenji Matsumoto
  • Organizer: AMERICAN SOCIETY FOR REPRODUCTIVE IMMUNOLOGY ANNUAL MEETING
  • Int'l Joint Research