自治医科大学博士（医学）令和4年度thesi

Chuluun-Erdene, Ariunbold

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Jichi Medical University Institutional Repository

（甲種）    論  文  要  旨   学 位 論 文    表 題 マクロファージのエフェロサイトシース過程における細胞内ATP動態に関する研究             申 請 者 氏 名 Ariunbold Chuluun-Erdene     担当指導教員氏名 武田 憲彦 教授       所 属 自治医科大学大学院医学研究科        地域医療学系専攻        循環病態・代謝学研究部           分子心血管病態学                        使用文字数  324    字          論  文  要  旨   氏名   Ariunbold Chuluun-Erdene     表題 マクロファージのエフェロサイトシース過程における細胞内ATP 動態に関する研究 The study of the spatio-temporal dynamics of intracellular ATP in macrophage efferocytosis １ 研究目的  Macrophages accumulate to hypoxic areas of inflammatory tissues and play central roles in clearing dead cells through efferocytosis. However, the intracellular energetic flow during efferocytosis under hypoxia remains largely unknown. My study aims to reveal spatio-temporal dynamics of intracellular energy currency, adenosine triphosphate (ATP), during efferocytosis in hypoxic macrophages. ２ 研究方法  I adopted a genetically encoded sensor, GO-ATeam, to fluorescently visualize intracellular ATP dynamics in macrophages under microscopic observation. Bone marrow-derived macrophages (BMDMs) were harvested from mice ubiquitously expressing GO-ATeam, and were co-cultured with apoptotic cells to assess intracellular ATP dynamics and cell clearance in efferocytosis under various conditions.  ３ 研究成果  I established the GO-ATeam imaging system to visualize cytosolic ATP dynamics in BMDMs. GO-ATeam imaging revealed that the cytosolic ATP level was locally elevated at a site of apoptotic cell engulfment in BMDMs under hypoxic conditions. Also, I found that efferocytosis was activated under the hypoxic conditions in a hypoxia-inducible factor 1 alpha (Hif-1α) manner. Immunofluorescent analysis showed that pyruvate kinase isozyme M2 (PKM2), a Hif-1α target enzyme, recruited at a site of apoptotic cell engulfment in BMDMs. Furthermore, efferocytosis was suppressed in BMDMs treated with a glycolysis inhibitor. ４ 考察  I obtained potent evidences that link intracellular ATP dynamics and glycolytic metabolism during efferocytosis in hypoxic macrophages. Engulfing apoptotic cells in efferocytosis requires drastic cytoskeleton remodeling, locally consuming a high amount of ATP. In this setting, glycolysis is beneficial to local ATP production and on-demand supply for its needs. This mechanism of local ATP production and supply might underpin efferocytosis activation under hypoxia where glycolytic metabolism is enhanced through several proteins including PKM2.  ５ 結論  I studied intracellular ATP dynamics and the metabolic status during macrophage efferocytosis under hypoxia. The collective data suggested that glycolytic metabolism is indispensable to activate efferocytosis programs in macrophages, boosting the clearance of apoptotic and dead cells under hypoxic conditions. My study would provide new insights to explain how macrophages efficiently conduct efferocytosis in hypoxic disease settings where oxygen lacks for the efficient production of ATP in mitochondria.  

The study of the spatio-temporal dynamics of intracellular ATP in macrophage efferocytosis

https://jichi-ir.repo.nii.ac.jp/record/2000081/files/%E3%80%90%E7%94%B2%E7%A8%AE%E3%80%91%E5%AD%A6%E4%BD%8D%E8%AB%96%E6%96%87_689%20Chuluun-Erdene%20Ariunbold%E6%B0%8F%EF%BC%88%E8%A6%81%E7%B4%84%EF%BC%89.pdf

The study of the spatio-temporal dynamics of intracellular ATP in macrophage efferocytosis

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