Molecular mechanism of hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08732
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ITOH Michiko 東京医科歯科大学, 大学院医歯学総合研究科, ジョイントリサーチ講座准教授 (00581860)
• Research Collaborator: SUGANAMI takayoshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 慢性炎症 / マクロファージ / crown-like structure

Outline of Final Research Achievements

We have reported a histological structure, termed hepatic crown-like structure (hCLS), in which CD11c-positive macrophages surround dead hepatocytes, a prominent feature of NASH using murine model of non-alcoholic steatohepatitis. In this study, we demonstrated that hCLS-constituting macrophages could be a novel macrophage subset that drives hepatocyte death-triggered liver fibrosis. We also showed that resident macrophages are a major cellular source of CD11c-positive macrophages constituting hCLS, which exhibited gene expression profiles distinct from CD11c-negative macrophages scattered in the liver. Moreover, depletion of CD11c-positive macrophages abolished hCLS formation and fibrogenesis in NASH. This study sheds light on the role of resident macrophages, in addition to recruited macrophages, in the pathogenesis of NASH.

Free Research Field

代謝学

Academic Significance and Societal Importance of the Research Achievements

慢性炎症を基盤とする様々な生活習慣病の病態形成においてマクロファージが重要な役割を果たすことが知られているが、マクロファージは非常に多様性の高い細胞集団であり、最近では病態形成に直接的な役割を果たす「疾患特異的マクロファージ」と理解が求められている。NASHの肝臓におけるCD11c陽性マクロファージは病理学的構造に基づく疾患特異的マクロファージと考えられ、その活性化機構および病態生理的意義の解明により、新規バイオマーカーや治療標的の開発に繋がることが期待される。