Ischemic Conditioning Promotes Transneuronal Survival and Stroke Recovery via CD36-Mediated Efferocytosis.

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Circulation research Pub Date : 2025-02-28 Epub Date: 2025-01-31 DOI:10.1161/CIRCRESAHA.124.325428
Hyunwoo Ju, Il-Doo Kim, Ina Pavlova, Shang Mu, Keun Woo Park, Joseph Minkler, Ahmed Madkoor, Wei Wang, Xiaoman Wang, Zhuhao Wu, Jiwon Yang, Maria Febbraio, John W Cave, Sunghee Cho
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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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)High 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.

Conclusions: 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.

远端缺血调节通过cd36介导的Efferocytosis减轻经神经元变性并促进脑卒中恢复。
背景:远端缺血调节(RIC)参与了包括脑卒中在内的脑血管疾病的跨器官保护。然而,缺乏共识的方案和对RIC临床治疗结果的争议表明对RIC的机制理解不足。目前的研究发现,在实验性脑缺血中,ric诱导的血液分子和细胞事件可促进长期功能恢复。方法:在脑卒中后2小时,随机选取幼稚小鼠和短暂性缺血性脑卒中小鼠进行假性条件反射或后肢RIC。在中风后3天,分析血液中的单核细胞组成,并检查脑组织中单核细胞来源的巨噬细胞(Mφ), efferocytosis水平和CD36表达。在单核细胞/ m - φs中特异性缺失CD36的小鼠被用来确定CD36在ricc介导的脑卒中后efferocytosis、transneuronal变性和恢复的调节中的作用。结果:脑卒中后2小时应用RIC增加了单核细胞进入损伤脑的数量。在缺血后的大脑中,Mφ具有CD36表达水平升高和effocylosis。这些脑Mφ的变化来源于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,并将单核细胞转移到促炎的ly6high状态。Mφ中CD36的条件缺失消除了ric诱导的血液单核细胞移位和脑内的efferocytosis。在中风恢复期,RIC挽救了野生型小鼠黑质中酪氨酸羟化酶+神经元的体积损失和行为缺陷,但在单核细胞/ m - φs中特异性缺失CD36的小鼠中则没有。结论:RIC诱导单核细胞向促炎状态转移,CD36水平升高,这与m - δ s中CD36依赖性efferocytosis有关,可挽救脑缺血后延迟的跨神经元变性并促进卒中恢复。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。
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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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