Novel mechanisms suppressing the pro-resolving phenotype of peripheral innate immunity following traumatic brain injury

摘要 神经炎已成为继发性损伤和疾病进展的关键组成部分 脑部创伤。最近的临床前研究揭示了外周先天免疫的神经毒性效应。 我们的初步发现表明，这种过度热情的反应可能是由EphA4/mTOR信号介导的 负向调节外周血单核/巨噬细胞(PDMS)的抗炎状态。这个 这项应用的研究目标是表征其背后的细胞和分子机制(S 先天免疫和丙二醛极化状态在组织损伤和功能恢复调节中的作用 TBI。我们的建议建立在广泛的初步和公开数据的基础上，这些数据表明， 在没有外周EphA4的情况下，使用对照嵌合小鼠降低促炎反应 皮质撞击(CCI)损伤。有趣的是，来自EphA4基因缺失小鼠的PDMS直接赋予神经保护和 单核细胞耗竭和置换模型中血脑屏障的保存。此外，我们发现， Pdm特异的EphA4抑制参与mTOR途径的关键蛋白的磷酸化，一种新的 PDMS预解析状态的介体。我们假设EphA4介导先天促炎 通过抑制mTOR信号而产生的免疫应答，而mTOR信号可诱导PDM的侵袭、极化和表型 导致脑外伤后神经血管功能障碍的行为。我们将使用特定于细胞的耗尽，以及 替代以及新的转基因小鼠模型。这些方法将包括严格的行为、 组织学和创新性低投入全基因组表观基因组和转录组的相关性评估 和产品数据管理行为的机理(S)。我们还将提供一个框架，用于重组神经炎性疾病 促进脑损伤后恢复和抑制促炎过程的反应。

ABSTRACT Neuroinflammation has emerged as a critical component of secondary injury and disease progression following brain trauma. Recent pre-clinical studies have shed light on the neurotoxic effects of peripheral innate immunity. Our preliminary findings suggest this overzealous response may be mediated by EphA4/mTOR signaling which negatively regulates the anti-inflammatory state of peripheral-derived monocyte/macrophages (PDMs). The research objective of this application is to characterize the cellular and molecular mechanism(s) underlying innate immunity and PDM polarization status in the regulation of tissue damage and functional recovery following TBI. Our proposal builds upon extensive preliminary and published data demonstrating a distinct protective and reduced pro-inflammatory response in the absence of peripheral EphA4 using chimeric mice following controlled cortical impact (CCI) injury. Interestingly, PDMs-derived from EphA4null mice directly confer neuroprotection and blood brain-barrier preservation in a model of monocyte depletion and replacement. Moreover, we discovered that PDM-specific EphA4 suppresses phosphorylation of key proteins involved in the mTOR pathway, a novel mediator of the pro-resolving state of PDMs. We hypothesize that EphA4 mediates the pro-inflammatory innate immune response by suppressing mTOR signaling, which induces PDM infiltration, polarization and phenotypic behaviors that drive neurovascular dysfunction following TBI. We will employ cell-specific depletions, and PDM replacement as well as novel transgenic murine models. These approaches will include rigorous behavioral, histological and innovative low-input genome-wide epigenomic and transcriptomic assessment of the relevance and mechanism(s) of PDM behaviors. We will also provide a framework for retooling the neuroinflammatory response to accelerate recovery and dampen pro-inflammatory processes after TBI.