探討內質網壓力如何調控巨噬細胞及其粒線體呼吸作用

How ER stress modulates different macrophage polarization and their mitochondria status.

林恬伊(Tianyi-Yi Lim)

指導教授 ： 蔡欣祐

國立臺灣大學/醫學院/分子醫學研究所/碩士(2020年)

https://doi.org/10.6342/NTU202003707

摘要

巨噬細胞是一個具有高度可塑性的先天性免疫細胞，在病原體防禦和組織修復的中扮演重要的角色。巨噬細胞在接受不同環境刺激後會活化為兩種不同的狀態： 促進發炎狀態(M1)或是抗發炎狀態(M2)。先前研究指出內質網壓力所產生的ER Unfolded protein response(ER-UPR，未摺疊蛋白反應)參與在巨噬細胞的活化過程中，但是目前對於內質網壓力如何影響巨噬細胞活化仍有爭議。同時，細胞內養份的代謝途徑也會因巨噬細胞的活化而改變。M1 巨噬細胞主要依賴糖解作用來產生能量，同時會阻斷檸檬酸循環；M2 巨噬細胞則會透過氧化脂肪酸來促進粒線體的呼吸作用進而產生能量。因此，本研究的目的是想要利用檢測粒腺體呼吸作用(mt-ROS)的活性來區分不同狀態的巨噬細胞，並且藉此來了解在ER-UPR失效的情況下粒線體呼吸作用的活性是否參與巨噬細胞活化。我們研究發現,M2 巨噬細胞相較於M0有較高的mt-ROS，則M1巨噬細胞有較的的mt-ROS。接著，在不朽化骨髓源性巨噬細胞(immortalized BMDMs) 基因敲弱(gene silenncing，基因沉默)來抑制UPR 途經中幾個重要的蛋白。希望在接下來的研究中，藉由這個系統可以讓我們釐清內質網壓力所產生的UPR會如何影響巨噬細胞活化以及粒線體呼吸作用。

關鍵字

巨噬細胞活化 ； 內質網壓力 ； 粒線體呼吸作用

並列摘要

Macrophages are high plasticity innate immune cells which are important for host defenses and maintain tissue homeostasis, by polarizing into two statuses; pro-inflammatory(M1) profile or anti-inflammatory(M2), respectively. Endoplasmic reticulum (ER) stress responses have been reported to participate in macrophage polarization. The regulation between ER stress responses and macrophage polarization is controversial, although they had been studied for a while. Moreover, the metabolic profile has also shown affected by macrophage polarization. For instance, M1 macrophage mainly produces energy by aerobic glycolysis but broken TAC cycle, whereas M2 macrophage prefers fatty acid oxidation(FAO) and oxidative phosphorylation(OXPHOS). Therefore, the goal for this study is to generate mitochondria detection system to distinguish naïve, M1 and M2 macrophage using the differences in their respiratory status and further examine whether there is a similar correlation between mitochondria respiratory status(mt-ROS) and macrophage polarity in ER-UPR defective system. In our finding, we had detected the strongest mt-ROS level in M2 macrophage follow by naïve and M1 macrophage. Then, we generated knocking down key protein in the major ER stress response pathway in immortalized bone marrow cell lines. Our ongoing data will help to clarify whether and how ER stress participates in macrophage polarization as well as their differential mtROS response.

並列關鍵字

Macrophage polarization ； ER stress response ； Mitochondrial respiratory status

參考文獻

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