The role of microglia in ischemic preconditioning.
The role of microglia in ischemic preconditioning.
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DOI：
10.1002/glia.23695
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发表时间：
2020-03
期刊：
影响因子：
6.2
通讯作者：
Weinstein, Jonathan R.
中科院分区：
文献类型：
--
作者：
McDonoug, Ashley;Weinstein, Jonathan R.
缺血预处理（IPC）是一种短暂的缺血刺激对随后的长期缺血事件产生保护作用的实验现象。最初认为是由于神经元的机械变化，我们对IPC的理解已经发展到包括短暂缺血/再灌注后CNS的全局重编程，其需要先天免疫信号传导途径，包括Toll样受体（TLR）和I型干扰素。小胶质细胞是CNS驻留的神经免疫细胞，表达这些关键的先天免疫受体。研究表明，IPC介导的神经元和轴突保护需要小胶质细胞。靶向TLR的多个范例已经汇聚在小胶质细胞中独特的I型干扰素反应上，这对于预处理介导的抗缺血保护至关重要。这些途径可以通过TLR激动剂、细胞因子（包括干扰素-β）和通过交叉耐受机制诱导预处理的药剂来靶向。转录组学分析和单细胞RNA研究指向小胶质细胞中的特定基因表达特征，其在功能上将这些可变细胞转变为免疫调节或保护表型。尽管存在技术挑战和知识空白需要克服，但靶向小胶质细胞中的特定分子信号通路是开发新型有效的卒中药物疗法的有希望的方向。在动物模型（包括非人灵长类动物）中进行的预处理研究显示，预处理有望作为选定的高危患者人群的预防性预处理治疗。此外，我们对IPC介导的保护机制的理解不断加深，正在确定新的细胞和分子靶点，用于治疗干预，可广泛应用于急性卒中和慢性血管性认知障碍患者。
Ischemic preconditioning (IPC) is an experimental phenomenon in which a brief ischemic stimulus confers protection against a subsequent prolonged ischemic event. Initially thought to be due to mechanistic changes in neurons, our understanding of IPC has evolved to encompass a global reprogramming of the CNS after transient ischemia/reperfusion that requires innate immune signaling pathways including Toll-like receptors (TLRs) and type I interferons. Microglia are the CNS resident neuroimmune cells that express these key innate immune receptors. Studies suggest that microglia are required for IPC-mediated neuronal and axonal protection. Multiple paradigms targeting TLRs have converged on a distinctive type I interferon response in microglia that is critical for preconditioning-mediated protection against ischemia. These pathways can be targeted through administration of TLR agonists, cytokines including interferon-β, and pharmaceutical agents that induce preconditioning through cross tolerance mechanisms. Transcriptomic analyses and single cell RNA studies point to specific gene expression signatures in microglia that functionally shift these mutable cells to an immunomodulatory or protective phenotype. Although there are technological challenges and gaps in knowledge to overcome, the targeting of specific molecular signaling pathways in microglia is a promising direction for development of novel and effective pharmacotherapies for stroke. Studies on preconditioning in animal models, including non-human primates, show promise as prophylactic preconditioning treatments for selected at risk patient populations. In addition, our growing understanding of the mechanisms of IPC mediated protection is identifying novel cellular and molecular targets for therapeutic interventions that could apply broadly to both acute stroke and chronic vascular cognitive impairment patients.
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影响因子：
9.3
作者：
Pena-Philippides JC;Caballero-Garrido E;Lordkipanidze T;Roitbak T
通讯作者：
Roitbak T
影响因子：
6.2
作者：
Cox DJ;Field RH;Williams DG;Baran M;Bowie AG;Cunningham C;Dunne A
通讯作者：
Dunne A
影响因子：
6.9
作者：
Bahjat FR;Alexander West G;Kohama SG;Glynn C;Urbanski HF;Hobbs TR;Earl E;Stevens SL;Stenzel-Poore MP
通讯作者：
Stenzel-Poore MP
影响因子：
--
作者：
DAHL, NA;BALFOUR, WM
通讯作者：
BALFOUR, WM
DOI：
10.1097/00004647-200008000-00004
发表时间：
2000-08-01
影响因子：
6.3
作者：
Bordet, R;Deplanque, D;Dupuis, B
通讯作者：
Dupuis, B