Role of ASC in TBI-Mediated Systemic Inflammation.

项目总结 本项目的总体目标是确定脑外伤引起的炎性改变是否会导致外周血管病变 依赖于细胞外小泡(EV)和ASC激活炎症小体的器官损害 斑点。我们最近的工作表明，脑创伤诱导的全身炎症反应的一个关键部分 包括释放含有大量天然免疫蛋白的细胞外小泡，这些天然免疫蛋白是由 受损的中枢神经系统(CNS)组织。重要的是，来自脑外伤动物的EV和ASC斑点诱导 周围器官中的炎性小体激活。这项提案的具体目标将决定蜂窝和 EV和ASC SPECK介导的天然免疫炎性反应的分子调控机制 颅脑损伤后外周脏器损伤。这项研究的假设是EV和ASC斑点在 脑外伤后通过携带炎症体蛋白到外周器官的先天免疫信号，从而导致组织 受伤。此外，用单抗中和分泌的ASC会减少外周器官。 颅脑损伤后的损伤，导致组织病理学结果的改善。目标1将确定TBI是否改变了 EV蛋白在脑、外周器官和体液中的组成。这些研究将描绘出一种蛋白质 颅脑损伤后肠病毒蛋白的变化。目标2将确定ASC斑点是否在大脑和外周器官中积累 颅脑损伤后可诱发炎症反应，导致下垂。我们将调查是否 体内炎性小体的激活会导致ASC斑点的出现，以及是否会沉积 组织中的ASC斑点诱导中性粒细胞和淋巴细胞的募集，从而有助于 周围器官的炎性环境。目标3将确定抗体中和的治疗效果 炎性小体对颅脑损伤后组织病理学结果的影响。这些研究将提供关键信息 关于中枢神经系统中EV和ASC斑点调节的天然免疫激活模式，并鉴定 相关的治疗目标，以控制脑外伤后的炎症和其他神经退行性疾病。

PROJECT SUMMARY The overall goal of this project is to determine whether TBI-induced inflammatory changes result in peripheral organ damage that is dependent on activation of the inflammasome by extracellular vesicles (EV) and ASC specks. Our recent work has shown that a crucial part of the TBI-induced systemic inflammatory response involves release of extracellular vesicles containing a cargo of innate immune proteins that are secreted from damaged central nervous system (CNS) tissue. Importantly, EV and ASC specks from TBI animals induce inflammasome activation in peripheral organs. The specific aims of this proposal will determine the cellular and molecular mechanisms regulating EV- and ASC speck-mediated innate immune inflammatory reactions in peripheral organs after TBI. The hypothesis of this study is that EV and ASC specks play a central role in innate immune signaling by carrying inflammasome proteins to peripheral organs after TBI, thus causing tissue injury. Moreover, neutralization of secreted ASC with a monoclonal antibody decreases peripheral organ damage after TBI, resulting in improved histopathological outcomes. Aim 1 will determine if TBI alters the composition of EV proteins in brain, peripheral organs and bodily fluids. These studies will delineate a protein profile of EV proteins after TBI. Aim 2 will establish if ASC specks accumulate in brain and peripheral organs after TBI and induce an inflammatory responses leading to pyroptosis. We will investigate whether the activation of inflammasomes in vivo leads to the appearance of ASC specks and whether the deposition of ASC specks in tissues induces the recruitment of neutrophils and lymphocytes, thus contributing to the inflammatory milieu in peripheral organs. Aim 3 will determine the therapeutic effects of antibody neutralization of the inflammasome on histopathological outcomes after TBI. These studies will provide critical information about the activation patterns of innate immunity regulated by EV and ASC specks in the CNS, and identify relevant therapeutic targets to control inflammation following TBI and other neurodegenerative disorders.