Alarmin-mediated control of CNS infection

项目总结 基金奖(R01NS112516)的重点是警报在激活先天性免疫反应中的作用。 大脑。我的实验室已经研究了两种警报因子IL-1a和IL-33的作用，它们独立地触发 炎症和对脑部感染的保护性免疫。有趣的是，IL-1a和IL-33共有一个共同的- 受体，白介素1受体辅助蛋白(IL-1RAP)。与阿尔茨海默病(AD)和 根据这一行政补充申请，il1rap中的SNP与AD进展有关， 淀粉样斑块的积累，并减少大脑中的炎症。这些发现也牵涉到 通过IL-1RAP(IL-1、IL-33和较少研究的IL-36家族)结合和发送信号的警报器的作用 成员)，在健康细胞中表达的分子，在细胞死亡时释放并启动局部 发炎。值得注意的是，全基因组关联研究也发现il1a和il33中的SNP与AD有关，但是 在较小程度上。综上所述，几项人类基因研究表明， AD的进展。我的实验室一直在研究警报的表达、感知和重要性 在大脑里呆了好几年。我们对这些分子如何提高免疫力有广泛的了解 并拥有独特的工具来了解阿尔茨海默病的警报生物学。重要的是，我们发现警报员 在感染期间激活大脑，促进外周免疫细胞进入中枢神经系统，尤其是 吞噬单核细胞来源的巨噬细胞。我们假设警报信号是必要的以促进 增强了AD大脑中的吞噬功能。为了检验这一假设，我们提出了三个目标，它们反映了 有资金的申请。

PROJECT SUMMARY The funded award (R01NS112516) focuses on the role of alarmins in activating innate immune responses in the brain. My laboratory has studied the role of two alarmins, IL-1a and IL-33, that independently trigger inflammation and protective immunity against a brain infection. Interestingly, IL-1a and IL-33, share a co- receptor, interleukin-1 receptor accessory protein (IL-1RAP). Of relevance to Alzheimer’s Disease (AD) and the basis of this administrative supplement application, SNPs in il1rap have been associated with AD progression, the accumulation of amyloid plaques, and decreased inflammation in the brain. These findings also implicate the role for alarmins that bind and signal through IL-1RAP (IL-1, IL-33, and the lesser studied IL-36 family members), molecules expressed in healthy cells that are released upon cell death and initiate local inflammation. Of note, genome-wide association studies have also implicated SNPs in il1a and il33 in AD, but to a lesser degree. Taken together, several human genetic studies have implicated aberrant alarmin sensing in the progression of AD. My laboratory has been studying the expression, sensing, and importance of alarmins in the brain for several years. We have an extensive understanding of how these molecules promote immunity to infection and have unique tools to understand alarmin biology in AD. Importantly, we find that alarmins activate the brain to promote the entry of peripheral immune cells to the CNS during infection, especially phagocytic monocyte-derived macrophages. We hypothesize that alarmin signaling is necessary to facilitate enhanced phagocytosis in the AD brain. To test this hypothesis, we propose three aims that mirror those of the funded application.