Mechanisms of chronic inflammation on the axis of cellular cholesterol metabolism

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03679
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Nippon Medical School
• Principal Investigator: Oishi Yumiko 日本医科大学, 大学院医学研究科, 大学院教授 (80435734)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: マクロファージ

Outline of Final Research Achievements

Macrophages maintain systemic homeostasis and regulate the pathogenesis of chronic inflammation, which is the basis of atherosclerosis. Previously, I have found that the immune response as a cellular function of macrophages is closely linked to cellular metabolism. Therefore, in this study, I examined the intracellular cholesterol metabolism of macrophages with the aim of establishing an anti-atherosclerosis treatment and prevention method. When macrophages were stimulated with TLR4 agonist LPS, free cholesterol was accumulated in lysosomes. When the cholesterol efflux was enhanced using a novel compound called polyrotaxan (PRX), not only macrophage's inflammatory response was suppressed, but also the formation of atherosclerotic plaques was inhibited in Ldlr-/- mice. These results suggested that intracellular cholesterol metabolism in macrophages can modulate macrophage function and inhibit the formation of atherosclerotic plaques.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

今回の検討から、マクロファージの細胞内コレステロール代謝を制御することによってマクロファージの機能を調節できること、マクロファージの細胞内コレステロールの蓄積を抑制すると動脈硬化プラークの形成を制御できることが明らかとなった。また、健常人および動脈硬化症例を対象とした検討から、単球中コレステロールは、頚動脈内膜厚に示される動脈硬化の進展度と正の相関を示し、多変量解析の結果、血中LDLとは独立した予後規定因子であった。これらのことから、ヒトにおいても単球/マクロファージの機能は細胞内コレステロール量と連携して制御され、単球コレステロール量は動脈硬化の重症度の指標となりうることが示唆された。