Role of ASC in TBI-Mediated Systemic Inflammation.

项目摘要 本项目的总体目标是确定TBI诱导的炎症变化是否导致外周血淋巴细胞的凋亡。 依赖于细胞外囊泡（EV）和ASC激活炎性小体的器官损伤 斑点。我们最近的研究表明，TBI诱导的全身炎症反应的一个关键部分， 涉及释放含有先天免疫蛋白货物的细胞外囊泡，所述先天免疫蛋白货物是从 中枢神经系统（CNS）组织受损。重要的是，来自TBI动物的EV和ASC斑点诱导 外周器官炎性小体激活。该提案的具体目标将决定蜂窝和 调节EV和ASC斑点介导的先天免疫炎症反应的分子机制 TBI后的外周器官这项研究的假设是，EV和ASC斑点发挥核心作用， 先天性免疫信号传导通过在TBI后将炎性体蛋白携带到外周器官，从而引起组织损伤。 损伤此外，用单克隆抗体中和分泌的ASC减少了外周器官 TBI后的损伤，导致改善的组织病理学结果。目标1将确定TBI是否会改变 脑、外周器官和体液中EV蛋白的组成。这些研究将描绘出一种蛋白质 TBI后EV蛋白的谱。目的2将确定ASC斑点是否在大脑和外周器官中积累 并诱导炎症反应导致焦亡。我们将调查 体内炎性小体的激活导致ASC斑点的出现， 组织中的ASC斑点诱导嗜中性粒细胞和淋巴细胞的募集，从而有助于细胞增殖。 周围器官的炎症环境。目的3将确定抗体中和的治疗效果 炎性小体对TBI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由EV和ASC斑点调节的先天免疫的激活模式，并确定 相关的治疗靶点，以控制TBI和其他神经退行性疾病后的炎症。

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.