Glial immune signaling in radiation-induced brain injury

摘要：放射性脑损伤中的神经胶质免疫信号传导。 用于治疗CNS癌症的颅放射疗法（CRT）经常导致非预期的和非预期的并发症。 使人衰弱的认知障碍CRT也仍然是对抗大脑的标准治疗 其他侵袭性癌症的转移。然而，分子和细胞机制 CRT引起的认知功能下降是多方面的， 解决了我们过去的研究结果表明，全脑急性CRT诱导进行性 神经退行性变化，包括氧化应激，神经发生减少， 神经炎症小胶质细胞和星形胶质细胞通过修剪在CNS中形成复杂的胶质细胞网络 并维持着数千个积极参与认知的突触。然而， 显示CRT诱导的认知障碍与星形胶质细胞肥大， 星形胶质细胞增生基因的表达和啮齿动物模型中持续的小胶质细胞活化。因此，我们认为， 我们假设有害的神经胶质信号传导显著地导致认知缺陷。的 补体系统是胶质细胞活化的有效介质，但它也具有一系列非- CNS中的免疫功能，包括突触修剪和清除凋亡细胞， 如果失调则是有害的细胞碎片。特别是，表达式中的全局高程 在神经退行性疾病中，已报道了CNS中补体C1 q和C3的表达。我们 研究结果表明，急性，全脑CRT介导的慢性小胶质细胞活化和反应性 星形胶质细胞，补体蛋白（C1 q，C3）和特异性受体的共表达升高 （C5 aR 1，TLR 4）与认知障碍一致。反应性神经胶质增生已被证明 上调补体级联蛋白，这些蛋白对突触有破坏性， 神经变性我们假设，脑癌治疗诱导的异常激活， 胶质细胞补体级联导致认知缺陷。我们的假设得到了两个关键因素的支持。 针对上游（C1 q）和下游补体信号传导的初步数据集 (C5a)激活分支点。第一，暴露条件性小胶质细胞选择性C1 q（敲低） 接受CRT的小鼠没有表现出认知受损， 与辐射的WT小鼠相比。第二，用口服活性的、BBB可渗透的C5 a 受体（C5 aR 1）拮抗剂改善急性CRT诱导的认知功能障碍， 小胶质细胞的激活。我们的假设将使用临床 相关、分次、局灶性颅骨照射范例±替莫唑胺、转基因和胶质瘤- 同基因小鼠模型，以及旨在测试机制的药理学方法 和治疗干预以恢复受损动物的认知功能。

ABSTRACT: Glial immune signaling in radiation-induced brain injury. Cranial radiation therapy (CRT) for the treatment of CNS cancers often leads to unintended and debilitating cognitive impairments. CRT also remains the standard of care to counter brain metastases for other invasive cancers. However, the molecular and cellular mechanisms underlying CRT-induced cognitive decline are multifaceted and have not been completely resolved. Our past findings show that whole-brain, acute CRT induces progressive neurodegenerative changes, including oxidative stress, reduced neurogenesis, and increased neuroinflammation. Microglia and astrocytes form complex glial networks in the CNS by pruning and maintaining thousands of synapses that are actively involved in cognition. Yet, we have shown that CRT-induced cognitive disruption coincides with astrocytic hypertrophy, elevated expression of astrogliosis genes, and persistent microglial activation in rodent models. Therefore, we hypothesize that detrimental glial signaling significantly contributes to cognitive deficits. The complement system is a potent mediator of the glial activation, but it also has a range of non- immune functions in the CNS, including synaptic pruning and clearance of apoptotic cells and cellular debris which is detrimental if dysregulated. Particularly, global elevation in the expression of complement C1q and C3 in the CNS has been reported in neurodegenerative conditions. Our findings indicate that acute, whole-brain CRT-mediated chronic microglial activation and reactive astrocytes, elevated co-expression of complement proteins (C1q, C3) and specific receptors (C5aR1, TLR4) coincided with cognitive impairments. Reactive gliosis has been shown to upregulate complement cascade proteins that are destructive to synapses and associated with neurodegeneration. We hypothesize that brain cancer therapy-induced aberrant activation in the glial complement cascade leads to cognitive deficits. Our hypothesis is supported by two key preliminary data sets targeting complement signaling at the upstream (C1q) and the downstream (C5a) activation branch points. First, exposure of conditional microglia-selective C1q (knockdown) mice to CRT did not exhibit impaired cognition and showed a lack of neuroinflammation as compared to irradiated WT mice. Second, treatment with an orally active, BBB permeable, C5a receptor (C5aR1) antagonist ameliorated acute CRT-induced cognitive deficits and alleviated microglial activation in the irradiated brain. Our hypothesis will be addressed using a clinically relevant, fractionated, focal cranial irradiation paradigm ± temozolomide, transgenic and glioma- bearing syngeneic mouse models, and pharmacologic approaches designed to test mechanisms and therapeutic interventions to restore cognitive function in the impaired animals.