Role of BLT1 signaling in innate immune cells in liver repair

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15760
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kitasato University
• Principal Investigator: Kojo Ken 北里大学, 医学部, 助教 (20525414)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: BLT1 / 肝修復 / 免疫細胞

Outline of Final Research Achievements

The aims of the present study were to examine the roles of leukotriene B4 receptor (BLT1) in innate immune cells in liver repair after acetaminophen (APAP)-induced liver injury. We examined the role of BLT1 by comparing the responses of BLT1 knockout (BLT1-/-) mice and wild type (WT) mice in liver repair following APAP hepatotoxicity. Deletion of neutrophils delayed liver repair in APAP-treated WT mice. BLT1 deficiency delayed liver repair, associated with reduction in apoptotic neutrophils and restorative macrophages. Transfer of BLT1 deficient neutrophils impaired liver repair. Efferocytosis of apoptotic neutrophils was suppressed BLT1-/- mice. The stimulation of resolvin E1 promoted differentiation of macrophages to a restorative type in a BLT1 signaling dependent manner. These results indicate that BLT1 facilitates liver repair via resolvin E1-mediated efferocytosis of apoptotic neutrophils by reparative macrophages.

Free Research Field

消化器

Academic Significance and Societal Importance of the Research Achievements

本研究は好中球BLT1シグナルが急性炎症の進行にだけでなく、炎症収束や組織修復にも関与するという従来とは異なるBLT1シグナルの役割を解明するものである。炎症組織が修復する過程には浸潤好中球から発信されるメッセージをマクロファージが受容することが重要である。本研究は、BLT1シグナルがレゾルビンRvE1を介して好中球とマクロファージによる一連の肝修復過程を連結させる作用があることを明らかにした。生体反応カスケードを連動させるBLT1シグナル伝達作用の機序の一端がが解明されたことによって、今後、生理活性脂質による肝再生治療法の開発につながることが期待される。