Glial immune signaling in radiation-induced brain injury

摘要：胶质免疫信号在放射性脑损伤中的作用。 颅脑放射治疗(CRT)治疗中枢神经系统肿瘤经常导致意外和 使人衰弱的认知障碍。CRT也仍然是对抗大脑的标准护理 其他浸润性癌症的转移。然而，分子和细胞机制 CRT引起的认知功能下降是多方面的，而且还没有完全 解决了。我们过去的研究结果表明，全脑、急性CRT导致进展 神经退行性改变，包括氧化应激、神经发生减少和增加 神经炎。小胶质细胞和星形胶质细胞通过修剪在中枢神经系统形成复杂的神经胶质网络 以及维持数千个积极参与认知的突触。然而，我们有 显示CRT引起的认知障碍与星形细胞肥大相一致，升高 啮齿动物模型中星形胶质细胞增殖症基因的表达和持续的小胶质细胞激活。因此， 我们假设有害的神经胶质信号对认知缺陷有很大影响。这个 补体系统是神经胶质细胞激活的一个强有力的中介，但它也有一系列非 中枢神经系统的免疫功能，包括突触修剪和清除凋亡细胞和 细胞碎片，如果调节失调是有害的。特别是，表达式中的全局高程 补体C1q和C3在中枢神经退行性疾病中的作用已有报道。我们的 研究结果表明，急性全脑CRT介导的慢性小胶质细胞激活和反应 星形胶质细胞补体蛋白(C1q、C3)与特异性受体共表达升高 (C5aR1，TLR4)与认知损害相一致。反应性胶质细胞增生症已经被证明是 上调对突触具有破坏性并与之相关的补体级联蛋白 神经退行性变。我们假设脑癌治疗诱导的脑内异常激活。 神经胶质补体的级联反应导致认知缺陷。我们的假设得到两个关键因素的支持 针对上游(C1q)和下游的补充信令的初步数据集 (C5a)激活分支点。第一，条件性小胶质细胞选择性C1q的暴露(基因敲除) 接受CRT的小鼠没有表现出认知障碍，也没有表现出神经炎症。 与受辐射的WT小鼠相比。第二，使用口服活性、血脑屏障透性的C5a进行治疗。 C5aR1受体拮抗剂改善CRT所致的急性认知功能障碍 照射后脑内小胶质细胞的激活。我们的假设将在临床上得到解决 相关的，分次的，局部颅脑照射范例±替莫唑胺，转基因和胶质瘤- 具有同基因小鼠模型，以及为测试机制而设计的药理学方法 以及治疗干预，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.