Inflammasome activation and lymphatic dysfunction in traumatic brain injury

摘要 创伤性脑损伤每年影响全球数百万人，目前来自 世界卫生组织建议，到今年，脑外伤将成为导致死亡和残疾的第三大原因 2020年。尽管这是一个普遍而紧迫的全球医学问题，但我们对脑外伤病因学的理解 仍然不完整。淋巴系统需要适当地排出细胞碎片以维持组织 动态平衡和受损/应激信号的去除，包括受损的细胞和蛋白质聚集体， 来自器官的疾病与一系列疾病有关。与其他外周器官相比，我们的 了解中枢神经系统(CNS)淋巴引流缺陷是如何导致 对疾病的描述仍然很少。在这个项目中，我们将调查泄露的后果 脑膜淋巴功能在脑外伤发病机制中的作用在我们的初步研究中，我们发现TBI会导致 严重损害脑淋巴引流和先前存在的脑膜淋巴功能缺陷 使大脑易于在脑创伤后加重临床疾病。以确定受损者是否 清除内源性损伤/应激信号(例如，细胞碎片和坏死细胞)与 炎性信号，我们评估了颅脑损伤后炎性小体复合体的形成。炎症性小体 多蛋白寡聚平台，协调IL-1和IL-18的产生，以及一种炎症形式的 细胞死亡是对损伤/应激信号的反应。我们发现损伤导致的脑膜淋巴功能障碍 与脑损伤后脑内显著的炎性小体形成和堆积有关。而且，我们的 初步发现和其他人的工作表明炎性小体激活在脑损伤疾病中起关键作用 发病机制。根据这些集体发现，我们假设异常炎症体发出信号 脑膜淋巴功能障碍的结果在机制上参与了脑外伤的发病。为了测试这一点，我们 提出三个目标。在目标1中，我们将采用一系列尖端脑膜淋巴修补术。 确定脑引流调节如何影响脑损伤疾病进展的方法。在《目标2》中，威尔 确定炎性小体信号在脑膜淋巴功能障碍下游的程度 在机制上对脑外伤的病理有贡献。在第三个目标中，我们将研究中枢神经系统淋巴系统如何衰退 随着年龄的增长，这种情况会影响老年人的脑损伤疾病预后。这项研究具有创新性，因为它 将在我们理解大脑引流中断以及由此导致的 炎症体低聚物影响中枢神经系统疾病的进展。此外，我们的初步研究表明， 调节脑膜淋巴管和炎症体信号可能起到非常必要的作用 治疗颅脑损伤的治疗策略，这进一步强调了这些研究的翻译价值。

ABSTRACT Traumatic brain injury (TBI) affects millions of people worldwide every year and current estimates from the World Health Organization suggest that TBI will be the third leading cause of death and disability by the year 2020. Despite being a prevalent and pressing global medical issue, our understanding of TBI pathoetiology remains incomplete. Proper drainage of cellular debris by the lymphatic system is required to maintain tissue homeostasis and impaired removal of damage/stress signals, including damaged cells and protein aggregates, from organs has been linked to a spectrum of diseases. In comparison to other peripheral organs, our understanding of how our how defects in lymphatic drainage from the central nervous system (CNS) contribute to disease remains poorly described. In this project, we will investigate the consequences of compromised meningeal lymphatic function in TBI pathogenesis. In our preliminary studies, we found that TBI results in severely compromised brain lymphatic drainage and that pre-existing deficits in meningeal lymphatic function predisposes the brain to exacerbated clinical disease following brain trauma. To determine if the impaired clearance of endogenous damage/stress signals (e.g., cellular debris and necrotic cells) was associated with inflammatory signaling, we evaluated inflammasome complex formation in TBI. Inflammasomes are multiprotein oligomeric platforms that coordinate IL-1 and IL-18 production, as well as an inflammatory form of cell death in response to damage/stress signals. We find that injury-induced meningeal lymphatic dysfunction is associated with pronounced inflammasome formation and accumulation in the TBI brain. Moreover, our preliminary findings and work from others demonstrate critical roles for inflammasome activation in TBI disease pathogenesis. Given these collective findings, we hypothesize that aberrant inflammasome signaling that results from meningeal lymphatic dysfunction mechanistically contributes to TBI pathogenesis. To test this, we propose three aims. In Aim 1, we will employ a series of cutting-edge meningeal lymphatic modifying approaches to identify how modulation of brain drainage influences TBI disease progression. In Aim 2, will determine to what extent inflammasome signaling downstream of meningeal lymphatic dysfunction mechanistically contributes to TBI pathology. In the third Aim, we will investigate how CNS lymphatic decline that occurs with aging influences TBI disease outcomes in the elderly. This research is innovative because it will break new ground in our understanding of how disruptions in brain drainage and the resulting buildup of inflammasome oligomers influence CNS disease progression. Moreover, our preliminary studies suggest that modulation of the meningeal lymphatics and inflammasome signaling can potentially serve as much-needed therapeutic strategies to treat TBI, which further underscores the translational value of these studies.