Ju Hyunwoo, Kim Il-Doo, Pavlova Ina, Mu Shang, Park Keun Woo, Minkler Joseph, Madkoor Ahmed, Wang Wei, Wang Xiaoman, Wu Zhuhao, Yang Jiwon, Febbraio Maria, Cave John W, Cho Sunghee
Burke Neurological Institute, White Plains, NY (H.J., I.P., K.W.P., J.M., A.M., S.C.).
Feil Brain Mind Research Institute (H.J., S.M., K.W.P., W.W., X.W., Z.W., S.C.), Weill Cornell Medicine, New York, NY.
Circ Res. 2025 Feb 28;136(5):e34-e51. doi: 10.1161/CIRCRESAHA.124.325428. Epub 2025 Jan 31.
Remote ischemic conditioning (RIC) has been implicated in cross-organ protection in cerebrovascular disease, including stroke. However, the lack of a consensus protocol and controversy over the clinical therapeutic outcomes of RIC suggest an inadequate mechanistic understanding of RIC. The current study identifies RIC-induced molecular and cellular events in the blood, which enhance long-term functional recovery in experimental cerebral ischemia.
Naive mice or mice subjected to transient ischemic stroke were randomly selected to receive sham conditioning or RIC in the hindlimb at 2 hours post-stroke. At 3 days post-stroke, monocyte composition in the blood was analyzed, and brain tissue was examined for monocyte-derived macrophage (Mφ), levels of efferocytosis, and CD36 expression. Mouse with a specific deletion of CD36 in monocytes/Mφs was used to establish the role of CD36 in RIC-mediated modulation of efferocytosis, transneuronal degeneration, and recovery following stroke.
RIC applied 2 hours after stroke increased the entry of monocytes into the injured brain. In the postischemic brain, Mφ had increased levels of CD36 expression and efferocytosis. These changes in brain Mφ were derived from RIC-induced changes in circulating monocytes. In the blood, RIC increased CD36 expression in circulating monocytes and shifted monocytes to a proinflammatory Lymphocyte antigen 6 complex (LY6C) state. Conditional deletion of CD36 in Mφ abrogated the RIC-induced monocyte shift in the blood and efferocytosis in the brain. During the recovery phase of stroke, RIC rescued the loss of the volume and of tyrosine hydroxylase+ neurons in substantia nigra and behavioral deficits in wild-type mice but not in mice with a specific deletion of CD36 in monocytes/Mφs.
RIC induces a shift in monocytes to a proinflammatory state with elevated CD36 levels, and this is associated with CD36-dependent efferocytosis in Mφs that rescues delayed transneuronal degeneration in the postischemic brain and promotes stroke recovery. Together, these findings provide novel insight into our mechanistic understanding of how RIC improves poststroke recovery.
远程缺血预处理（RIC）已被证实与包括中风在内的脑血管疾病的跨器官保护有关。然而，缺乏统一的方案以及RIC临床治疗效果存在争议，这表明对RIC的机制理解不足。本研究确定了RIC在血液中诱导的分子和细胞事件，这些事件可促进实验性脑缺血后的长期功能恢复。
将未处理的小鼠或经历短暂性缺血性中风的小鼠随机分为两组，在中风后2小时接受假预处理或后肢RIC。中风后3天，分析血液中的单核细胞组成，并检查脑组织中的单核细胞衍生巨噬细胞（Mφ）、吞噬作用水平和CD36表达。使用单核细胞/Mφs中特异性缺失CD36的小鼠来确定CD36在RIC介导的吞噬作用调节、跨神经元变性和中风后恢复中的作用。
中风后2小时应用RIC可增加单核细胞进入受损脑内。在缺血后脑中，Mφ的CD36表达水平和吞噬作用增加。脑Mφ的这些变化源于RIC诱导的循环单核细胞的变化。在血液中，RIC增加了循环单核细胞中CD36的表达，并使单核细胞转变为促炎淋巴细胞抗原6复合物（LY6C）状态。Mφ中CD36的条件性缺失消除了RIC诱导的血液中单核细胞的转变和脑中的吞噬作用。在中风恢复阶段，RIC挽救了野生型小鼠黑质中体积和酪氨酸羟化酶+神经元的损失以及行为缺陷，但在单核细胞/Mφs中特异性缺失CD36的小鼠中则没有。
RIC诱导单核细胞转变为CD36水平升高的促炎状态，这与Mφ中依赖CD36的吞噬作用有关，后者可挽救缺血后脑中的延迟性跨神经元变性并促进中风恢复。总之，这些发现为我们对RIC如何改善中风后恢复的机制理解提供了新的见解。
