Regulation of atheroscllerosis by lymphatic endothelial calpain sysmtems

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08590
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Showa University
• Principal Investigator: Miyazaki Takuro 昭和大学, 医学部, 准教授 (80398693)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: カルパイン / リンパ管内皮細胞 / タンパク質分解 / 制御性T細胞 / 動脈硬化症

Outline of Final Research Achievements

This study investigated whether the calpain systems in lymphatic endothelial cells (LECs) associate with the LEC-lymphocyte interaction under hypercholesterolemia. Lipidomic analysis in hypercholesterolemic mice showed that several lysophospholipids, including lysophosphatidic acid (LPA), accumulated in the lymphatic environment. LPA enables the potentiation of calpain systems in cultured LECs, which limits their ability to stabilize regulatory T cells (Treg) without altering other T cell subsets. Targeting calpain systems in LECs expanded Tregs in the blood circulation under hypercholesterolemia, concomitant with the redistribution of Tregs in lymphoid organs. Moreover, LPA-induced calpain overactivation potentiated the IL-18/NF-kB/VCAM1 axis in LECs, thereby inhibiting lymphocyte mobility on the cells. Thus, calpain systems in LECs have a key role in controlling Treg stability and trafficking under hypercholesterolemia.

Free Research Field

血管生物学　循環器内科　内分泌代謝　栄養学　病態生化学

Academic Significance and Societal Importance of the Research Achievements

一連の結果から、リンパ管内皮細胞のカルパインシステムは、脂質異常症存在下のリンパ管の形態維持だけでなく、制御性T細胞の安定性や動態にも影響することが判明した。既報から、脂質異常症においてリンパ管がリポタンパク質や免疫細胞の輸送経路として重要であることは明らかとなっていたが、直接的な免疫細胞の制御に関わっていることは本研究において初めて解明された。本研究は、動脈硬化症の発症原因の包括的な理解に資するものと期待される。