Understanding and interfering with resident microglia activation following subarachnoid hemorrhage (SAH)

了解和干扰蛛网膜下腔出血(SAH)后驻留小胶质细胞的激活

基本信息

项目摘要

In our previous work, we have characterized CNS immune response after subarachnoid hemorrhage (SAH) as an activation of the innate immune system. Blood in the subarachnoid compartment creates a pro-inflammatory environment, leads to an activation of macrophages at the brain base and induces an inflammatory response at the perivascular space. This subsequently activates exclusively the resident CNS-specialized microglia (as shown by chimera experiments) in an outside-in fashion. Furthermore, we have demonstrated that secondary neuro-axonal injury after SAH is linked to microglia activation. Tumor-necrosis factor- α (TNF-α) has been identified as a primary candidate for mediating this inflammatory response. Besides, our preliminary work indicates that extracellular RNA (eRNA) and DNA accumulate in and around the brain after SAH and may mediate TNF-α liberation from microglia. eRNA has been shown to become released from cells under diverse pathological conditions (outside the CNS) and induces pro-inflammatory and vessel permeability-inducing processes. Thus, eRNA is a target for modulating myeloid cell effector functions. In the herein presented project, we first aim at understanding the phenotype and function of activated microglia after SAH in more detail. Therefore, we will characterize their inflammatory phenotype and further study the impact of these effector cells on the pathological hallmarks of SAH, i.e. early loss of blood-brain barrier (BBB) function and delayed neuro-axonal injury. This will be achieved by a combination of expression profiling, in vitro cellular, electrophysiological and histoanalytical experiments. Secondly, we will assess the dynamics and mechanisms of eRNA accumulation in the subarachnoid space and brains after SAH. Here, we will stain mouse and human autopsy specimens for quantified content of eRNA and will identify the source of eRNA in a set of in vivo and in vitro experiments. In the third part, we will study study the mechanism of TNF-α liberation by microglia and its downstream signaling in vitro. We hypothesis that eRNA, released after SAH, is capable of stimulating the release of TNF-α from CNS macrophages/microglia and exerting effector functions, such as BBB damage and neuro-axonal cell death. In the fourth part, we will interfere with eRNA functions in vivo and will evaluate RNase1 and RNase Inhibitor as modulators of vascular homeostasis to control the function of eRNA after brain injury following SAH. To test this, we will use exogenous RNase1/RNase Inhibitor or transgenic EC-specific conditional knockouts of Rnase1 and RNase Inhibitor. Finally, we will evaluate novel therapeutic strategies to interfere with the activation of the innate immune system and the subsequent secondary brain injury following experimental SAH. Here, we will put our emphasis on pharmacological strategies that target (i) microglial cells and (ii) TNF-α, which have the potential to be rapidly translated into a clinical setting.
在我们以前的工作中,我们已经将蛛网膜下腔出血(SAH)后的CNS免疫反应表征为先天免疫系统的激活。蛛网膜下腔中的血液产生促炎环境,导致脑基底部巨噬细胞活化,并诱导血管周围空间的炎症反应。这随后以一种由外向内的方式激活了常驻的CNS特异性小胶质细胞(如嵌合体实验所示)。此外,我们已经证明,继发性神经轴索损伤后SAH与小胶质细胞激活。肿瘤坏死因子- α(TNF-α)已被确定为介导这种炎症反应的主要候选者。此外,我们的初步工作表明,SAH后细胞外RNA(eRNA)和DNA积聚在脑内和周围,并可能介导TNF-α从小胶质细胞释放。已显示eRNA在多种病理条件下(CNS外)从细胞中释放,并诱导促炎和血管通透性诱导过程。因此,eRNA是调节骨髓细胞效应子功能的靶标。在本项目中,我们首先旨在更详细地了解SAH后激活的小胶质细胞的表型和功能。因此,我们将表征它们的炎性表型,并进一步研究这些效应细胞对SAH病理标志的影响,即血脑屏障(BBB)功能的早期丧失和延迟的神经轴突损伤。这将通过表达谱分析、体外细胞、电生理和组织分析实验的组合来实现。其次,我们将评估SAH后蛛网膜下腔和大脑中eRNA积累的动力学和机制。在这里,我们将对小鼠和人类尸检标本进行染色,以获得定量的eRNA含量,并将在一组体内和体外实验中鉴定eRNA的来源。第三部分研究小胶质细胞释放TNF-α的机制及其下游信号转导。我们假设SAH后释放的eRNA能够刺激CNS巨噬细胞/小胶质细胞释放TNF-α,并发挥效应器功能,如BBB损伤和神经轴突细胞死亡。在第四部分中,我们将在体内干扰eRNA的功能,并将评估RNase 1和RNase Inhibitor作为血管稳态调节剂来控制SAH脑损伤后eRNA的功能。为了测试这一点,我们将使用外源RNase 1/RNase Inhibitor或转基因EC特异性条件敲除RNase 1和RNase Inhibitor。最后,我们将评估新的治疗策略,以干扰先天免疫系统的激活和随后的继发性脑损伤后,实验性SAH。在这里,我们将重点放在靶向(i)小胶质细胞和(ii)TNF-α的药理学策略上,这些策略有可能迅速转化为临床环境。

项目成果

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Professor Dr. Peter Vajkoczy其他文献

Professor Dr. Peter Vajkoczy的其他文献

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{{ truncateString('Professor Dr. Peter Vajkoczy', 18)}}的其他基金

Cell-specific roles of ephrin-B2 signaling in neurovascular repair and regeneration after ischemic injury of the brain
肝配蛋白 B2 信号在脑缺血损伤后神经血管修复和再生中的细胞特异性作用
  • 批准号:
    289426136
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
    Research Units
Interaction between the microglia and blood vessels in malignant brain tumors - significance for brain tumor angiogenesis, vascular modulation, and brain tumor growth
恶性脑肿瘤中小胶质细胞和血管之间的相互作用——对脑肿瘤血管生成、血管调节和脑肿瘤生长的意义
  • 批准号:
    22033510
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes
Etablierung einer neuartigen Thermodiffusions-Kathetersonde zur Messung des regionalen cerebralen Blutflusses (CBF) und Entwicklung eines CBF-basierten multimodalen Neuromonitoringsystems
建立一种用于测量局部脑血流(CBF)的新型热扩散导管探针并开发基于CBF的多模态神经监测系统
  • 批准号:
    5223256
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Pathophysiologic and therapeutic significance of EphrinB2/EphB4 for angiogenesis, microcirculation, and growth of malignant brain tumors
EphrinB2/EphB4 对血管生成、微循环和恶性脑肿瘤生长的病理生理学和治疗意义
  • 批准号:
    5191186
  • 财政年份:
    1999
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes

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Targeting Resident Cardiac Fibroblast Subpopulations for Protection Against Fibrosis
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克罗恩病中的 CD4 组织驻留记忆 T 细胞
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CD4+ Tissue resident memory T-cells in Crohnâs Disease
克罗恩病中的 CD4 组织驻留记忆 T 细胞
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  • 财政年份:
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Alcohol Regulation of Resident Vascular Stem Cells.
驻留血管干细胞的酒精调节。
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    9107329
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