Role of NLRP3 inflammasome in intestinal ischemia/reperfusion and subsequent acute lung injury

• Project/Area Number: 18K16329
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Jichi Medical University
• Principal Investigator: Inoue Yoshiyuki 自治医科大学, 医学部, 講師 (80375279)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: インフラマソーム / 炎症反応 / サイトカイン / 腸管虚血再灌流 / 肺血管内皮細胞 / 腸管虚血再灌流障害 / NLRP3インフラマソーム / 血管内皮細胞

Outline of Final Research Achievements

Intestinal ischemia/reperfusion (I/R) injury leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1-dependent release of IL-1β after I/R injury. Here, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1, or IL-1β prolonged survival after intestinal I/R injury. NLRP3 deficiency prevented intestinal I/R-induced acute lung injury (ALI) characterized by inflammation and vascular permeability. Bone marrow chimeric experiments showed that NLRP3 in non-bone marrow-derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to this process. These findings provide new insights into the mechanism underlying intestinal I/R-induced ALI, and suggest that endothelial NLRP3 inflammasome is a novel potential target for treating and preventing this disorder.

Academic Significance and Societal Importance of the Research Achievements

本研究により、肺血管内皮細胞におけるNLRP3インフラマソームが腸管I/R障害に続発する肺血管透過性の亢進による急性肺障害において重要な役割を果たしていることを明らかにした。腸管I/R障害と肺障害を繋ぐ新たな分子機序および新たな臓器連関機構の解明という点から、本研究の学術的な意義は大きいと考えられる。

Research Products

• [Journal Article] Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: potential role of ferroptosis. (2020)
  • Author(s): 3)Yamada N, Karasawa T, Wakiya T, Sadatomo A, Ito H, Kamata R, Watanabe S, Komada T, Kimura H, Sanada Y, Sakuma Y, Mizuta K, Sata N, Takahashi M
  • Journal Title: Am J Transplant Volume: - Issue: 6 Pages: 1606-1618
  • DOI: 10.1111/ajt.15773
  • Peer Reviewed / Open Access
• [Journal Article] GSDME-dependent incomplete pyroptosis (2020)
  • Author(s): Aizawa E, Karasawa T*, Watanabe S, Komada T, Kimura H, Kamata R, Ito H, Hishida E,
  • Journal Title: iScience Volume: －
  • Peer Reviewed / Open Access
• [Journal Article] Role of TLR5 in inflammation and tissue damage after intestinal ischemia-reperfusion injury. (2019)
  • Author(s): 7)Ito H, Sadatomo A, Inoue Y, Yamada N, Aizawa E, Hishida E, Kamata R, Karasawa T, Kimura H, Watanabe S, Komada T, Horie H, Kitagawa J, Sata N, Takahashi M
  • Journal Title: Biochem Biophys Res Commun Volume: 519 Issue: 1 Pages: 15-22
  • DOI: 10.1016/j.bbrc.2019.08.083
  • Peer Reviewed / Open Access
• [Journal Article] Crucial role of NLRP3 inflammasome in the development of peritoneal dialysis-related peritoneal fibrosis. (2019)
  • Author(s): 6)Hishida E, Ito H, Komada T, Karasawa T, Kimura H, Watanabe S, Kamata R, Aizawa E, Kasahara T, Morishita Y, AkimotoT, Nagata D, Takahashi M
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 10363-10363
  • DOI: 10.1038/s41598-019-46504-1
  • Peer Reviewed / Open Access
• [Remarks] 自治医科大学 分子病態治療研究センター 炎症・免疫研究部
  • URL: http://www.jichi.ac.jp/inflammation/