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, Zhu Jieqing, Song Shan, Yang Moua, Brown Ashley Kaye, Xu Zhen, Ma Yan-Qing, Smith Brian C, Zielonka Jacek, Traylor James G, Ben Dhaou Cyrine, Orr A Wayne, Cui Weiguo, Chen Yiliang
Versiti Blood Research Institute, Milwaukee, WI, USA.
Versiti Blood Research Institute, Milwaukee, WI, USA.
J Lipid Res. 2025 May;66(5):100809. doi: 10.1016/j.jlr.2025.100809. Epub 2025 Apr 16.
Oxidized low-density lipoprotein (oxLDL) promotes proatherogenic phenotypes in macrophages, accelerating the progression of atherosclerosis. Our previous studies demonstrated that oxLDL binds to its receptor CD36, stimulating mitochondrial reactive oxygen species (mtROS), which are critical in atherosclerosis development. However, the mechanisms underlying mtROS induction and their effects on macrophage cellular functions remain poorly understood. Macrophages rely on phagocytosis to clear pathogens, apoptotic cells, or other particles, a process critical for tissue homeostasis. Dysregulated or excessive particle ingestion, a key step in phagocytosis, can lead to lipid overloading and foam cell formation, a hallmark of atherosclerosis. In this study, we showed that macrophages pretreated with oxLDL exhibit increased particle ingestion, a phagocytic response significantly attenuated in Cd36-null macrophages. Further investigations revealed that oxLDL-induced phagocytosis depends on mtROS, as their suppression inhibited the process. In vivo, atherosclerosis-prone Apoe-null mice on a high-fat diet exhibited increased mtROS levels and enhanced phagocytic activity in aortic foamy macrophages compared to those from chow diet-fed mice, supporting a role of mtROS in promoting lesional macrophage phagocytosis. Mechanistically, we identified a novel signaling pathway whereby oxLDL/CD36 interaction induces the translocation of the cytosolic enzyme pyruvate kinase muscle 2 (PKM2) to mitochondria. Disruption of PKM2 mitochondrial translocation using siRNA knockdown or a specific chemical inhibitor reduced mtROS production and attenuated oxLDL-induced phagocytosis. In conclusion, our findings reveal a novel oxLDL-CD36-PKM2 signaling axis that drives mtROS production and phagocytosis in atherogenic macrophages.
氧化型低密度脂蛋白（oxLDL）可促进巨噬细胞中促动脉粥样硬化表型的形成，加速动脉粥样硬化的进展。我们之前的研究表明，oxLDL与其受体CD36结合，刺激线粒体活性氧（mtROS），而mtROS在动脉粥样硬化发展过程中至关重要。然而，mtROS诱导的机制及其对巨噬细胞功能的影响仍知之甚少。巨噬细胞依靠吞噬作用清除病原体、凋亡细胞或其他颗粒，这一过程对组织稳态至关重要。吞噬作用的关键步骤——颗粒摄取失调或过度，可导致脂质超载和泡沫细胞形成，这是动脉粥样硬化的一个标志。在本研究中，我们发现用oxLDL预处理的巨噬细胞颗粒摄取增加，而这种吞噬反应在Cd36基因敲除的巨噬细胞中显著减弱。进一步研究表明，oxLDL诱导的吞噬作用依赖于mtROS，因为对mtROS的抑制会阻碍这一过程。在体内，与喂食普通饲料的小鼠相比，高脂饮食喂养的易患动脉粥样硬化的载脂蛋白E基因敲除小鼠主动脉泡沫巨噬细胞中的mtROS水平升高，吞噬活性增强，这支持了mtROS在促进病变巨噬细胞吞噬作用中的作用。从机制上讲，我们确定了一条新的信号通路，即oxLDL/CD36相互作用诱导细胞质酶丙酮酸激酶M2型（PKM2）向线粒体转位。使用小干扰RNA敲低或特定化学抑制剂破坏PKM2的线粒体转位，可减少mtROS的产生并减弱oxLDL诱导的吞噬作用。总之，我们的研究结果揭示了一条新的oxLDL-CD36-PKM2信号轴，该信号轴驱动致动脉粥样硬化巨噬细胞中的mtROS产生和吞噬作用。
