Neuronal IL-1R1 Signaling in Mild Closed Head Injury

摘要 众所周知，细胞因子白细胞介素-1（IL-1）介导外周血中的有害炎症过程。 组织中IL-1在年龄和神经退行性疾病中升高。因此，IL-1已成为主要焦点 治疗急性损伤和慢性损伤后神经炎症的抗炎策略 神经退行性疾病令人惊讶的是，很少有证据表明，神经元是通过直接的 IL-1的作用。相反，神经元特异性“非经典”IL-1受体（IL-1 R1）途径， 促进而不是侵蚀神经元的活力。尽管这种范式转变的观察， 非经典途径很少受到关注。关于神经元IL-1 R1 信号传导有助于大脑的炎症环境、突触生理学和认知功能， 从损伤和神经变性的进展中恢复。这种知识差距可能会破坏潜在的 神经保护方法的目标是抑制IL-1作为作用机制的一部分。 为了解决这一知识缺口，我们将使用新的小鼠模型，表现出神经元特异性调节IL-1 信令（即，IL-1 R1-floxed小鼠观察神经元特异性敲低，IL-1 R1-restored小鼠观察神经元特异性敲低。 IL-1 R1的神经元特异性表达）。我们的总体假设是，神经元IL-1 R1信号传导是 内在的保护。 我们将在以下具体目标中检验这一假设： SA 1定义神经元IL-1 R1通路在小鼠对CHI的炎症反应中的作用。 SA 2定义小鼠CHI后稳态突触可塑性中的神经元IL-1 R1通路。 SA 3确定神经元IL-1 R1在CHI后认知恢复中的时间作用。 如果我们的假设得到证实，我们将提供一种新的神经保护方法的知识， 开发现有抗炎干预措施的新制剂， IL-1的功能新的IL-1 R1疗法的开发将包括仅抑制IL-1 R1表达的药物。 IL-1 R1通路或仅激活神经保护性IL-1 R1通路。

ABSTRACT The cytokine interleukin-1 (IL-1) is well known to mediate detrimental inflammatory processes in peripheral tissues. IL-1 is elevated in age and in neurodegenerative disease. As a result, IL-1 has become a major focus of anti-inflammatory strategies to treat neuroinflammation following acute injury and in chronic neurodegenerative disease. Surprisingly, there is scant evidence that neurons are damaged through the direct actions of IL-1. To the contrary, a neuron-specific “non-canonical” IL-1 receptor (IL-1R1) pathway that promotes, rather than erodes, neuronal viability has been identified. Despite this paradigm-shifting observation, the non-canonical pathway has received little attention. Much remains unknown about how neuronal IL-1R1 signaling contributes to the brain's inflammatory milieu, synaptic physiology, and cognitive function, and recover from injury and progression of neurodegeneration. This knowledge gap could undermine potential neuroprotective approaches that target suppression of IL-1 as part of the mechanism-of-action. To address this knowledge gap, we will use novel mouse models exhibiting neuron-specific modulation of IL-1 signaling (i.e., IL-1R1-floxed mice to look at neuron-specific knockdown and IL-1R1-restore mice to look at the neuron-specific expression of IL-1R1). Our overarching hypothesis is that neuronal IL-1R1 signaling is inherently protective. We will test this hypothesis in the following Specific Aims: SA1 Define the role of the neuronal IL-1R1 pathway in the inflammatory response to a CHI in mice. SA2 Define the neuronal IL-1R1 pathway in homeostatic synaptic plasticity after a CHI in mice. SA3 Determine the temporal role of neuronal IL-1R1 in the cognitive recovery following a CHI. If our hypothesis is affirmed, we will provide knowledge of a new neuroprotective approach and enable the development of new formulations of existing anti-inflammatory interventions that preserve the neuroprotective functions of IL-1. The development of novel IL-1R1 therapies would include agents that only suppress the inflammatory IL-1R1 pathway or only activate the neuroprotective IL-1R1 pathway.