Zhang Jue, Chang Jackie, Chen Vaya, Beg Mirza Ahmar, Huang Wenxin, Vick Lance, Wang Yaxin, Zhang Heng, Yttre Erin, Gupta Ankan, Castleberry Mark, Zhang Ziyu, Dai Wen, Song Shan, Zhu Jieqing, Yang Moua, Brown Ashley Kaye, Xu Zhen, Ma Yan-Qing, Smith Brian C, Zielonka Jacek, Traylor James G, Dhaou Cyrine Ben, Orr A Wayne, Cui Weiguo, Zheng Ze, Chen Yiliang
bioRxiv. 2024 Jul 15:2023.09.07.556574. doi: 10.1101/2023.09.07.556574.
Macrophage efferocytosis, the process by which phagocytes engulf and remove apoptotic cells (ACs), plays a critical role in maintaining tissue homeostasis. Efficient efferocytosis prevents secondary necrosis, mitigates chronic inflammation, and impedes atherosclerosis progression. However, the regulatory mechanisms of efferocytosis under atherogenic conditions remain poorly understood. We previously demonstrated that oxidized LDL (oxLDL), an atherogenic lipoprotein, induces mitochondrial reactive oxygen species (mtROS) in macrophages via CD36. In this study, we demonstrate that macrophage mtROS facilitate continual efferocytosis through a positive feedback mechanism. However, oxLDL disrupts continual efferocytosis by dysregulating the internalization of ACs. This disruption is mediated by an overproduction of mtROS. Mechanistically, oxLDL/CD36 signaling promotes the translocation of cytosolic PKM2 to mitochondria, facilitated by the chaperone GRP75. Mitochondrial PKM2 then binds to Complex III of the electron transport chain, inducing mtROS production. This study elucidates a novel regulatory mechanism of efferocytosis in atherosclerosis, providing potential therapeutic targets for intervention.
Macrophages clear apoptotic cells through a process called efferocytosis, which involves mitochondrial ROS. However, the atherogenic oxidized LDL overstimulates mitochondrial ROS via the CD36-PKM2 pathway, disrupting continual efferocytosis. This finding elucidates a novel molecular mechanism that explains defects in efferocytosis, driving atherosclerosis progression.
巨噬细胞胞葬作用，即吞噬细胞吞噬并清除凋亡细胞（ACs）的过程，在维持组织稳态中起关键作用。高效的胞葬作用可防止继发性坏死、减轻慢性炎症并阻碍动脉粥样硬化进展。然而，在动脉粥样硬化形成条件下胞葬作用的调节机制仍知之甚少。我们之前证明，氧化型低密度脂蛋白（oxLDL），一种致动脉粥样硬化脂蛋白，通过CD36在巨噬细胞中诱导线粒体活性氧（mtROS）。在本研究中，我们证明巨噬细胞mtROS通过正反馈机制促进持续的胞葬作用。然而，oxLDL通过失调ACs的内化来破坏持续的胞葬作用。这种破坏由mtROS的过量产生介导。机制上，oxLDL/CD36信号传导促进胞质PKM2在伴侣蛋白GRP75的促进下转位至线粒体。线粒体PKM2然后与电子传递链的复合物III结合，诱导mtROS产生。本研究阐明了动脉粥样硬化中胞葬作用的一种新调节机制，为干预提供了潜在的治疗靶点。
巨噬细胞通过一种称为胞葬作用的过程清除凋亡细胞，该过程涉及线粒体ROS。然而，致动脉粥样硬化的氧化型低密度脂蛋白通过CD36-PKM2途径过度刺激线粒体ROS，破坏持续的胞葬作用。这一发现阐明了一种新的分子机制，解释了胞葬作用缺陷，推动动脉粥样硬化进展。
