Role of the interaction between dead cells and macrophages in the pathogenesis of NASH: focusing on phagocytosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16539
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Nagoya University
• Principal Investigator: Kanamori Yohei 名古屋大学, 環境医学研究所, 学振特別研究員(PD) (70838903)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: NASH / マクロファージ / 死細胞

Outline of Final Research Achievements

This study explored the role of dead cell-sensing in macrophages in the pathogenesis of NASH. Stimulation of macrophages with dead hepatocytes induced expression of proinflammatory and profibrotic factors in vitro. MiT/TFE transcription factors were activated in macrophages stimulated with dead cells.
siRNA-mediated silencing of MiT/TFE transcription factors suppressed expression of these genes in macrophages. Furthermore, immunostaining revealed that MiT/TFE transcription factors are activated in macrophages in NASH liver. Considering lysosomal stress activates MiT/TFE transcription factors, these results suggest that lysosomal stress triggered by phagocytosis of dead cells induces activation of MiT/TFE transcription factors in macrophages, leading to the development of hepatic fibrosis in NASH.

Free Research Field

病態医化学

Academic Significance and Societal Importance of the Research Achievements

本研究を通して、NASHにおいて死細胞認識によるマクロファージの機能変容を惹起する新たな細胞内シグナルが明らかになった。死細胞を貪食する過程でマクロファージには多様な細胞成分の流入が起こる可能性が想定されるため、今後、死細胞に由来するどの細胞成分がマクロファージの形質転換の引き金となるかについてさらなる解析が必要である。死細胞とマクロファージとの相互作用の分子機構を明らかにした本研究は、NASHの新たな病態メカニズムの解明に資すると期待される。