The Role of Dendritic Cells in Regulating the Gut-Brain Immune Axis in Ischemic Stroke

项目摘要/摘要 中风是一种流行的、毁灭性的疾病，治疗选择有限。炎症和 免疫细胞是缺血性卒中病理生理学的主要组成部分，在急性脑梗塞中起重要作用。 和延迟性组织损伤。然而，我们对免疫调节因素的了解还不够全面 脑缺血引发的反应仍然是发展有效的 基于调节缺血后炎症的治疗干预。除了激活大脑之外 常驻免疫细胞，缺血性卒中的特点是外周血与生俱来和 参与炎症反应并造成损害的适应性免疫细胞。 分布在上皮表面的共生微生物群在免疫形成中起着决定性的作用。 系统，它的开发、维护和功能在很大程度上依赖于相关的 不同微生物种类的丰度和组成。特别是，肠道共生 细菌，体内最丰富的共生室，已经成为一种强有力的调节器 对中风的免疫反应。这项研究计划的长期目标是阐明 肠道微生物区系在卒中病理生物学中的研究及开发新的实验框架 缺血性中风的预防和治疗方法。在本应用程序中，我们将测试 假设共生肠道微生物区系与树突状细胞的相互作用是关键 调节免疫系统和炎症反应对中风预后的决定因素 脑缺血。在相关初步结果的支持下，这一应用程序将检验该假设 共生肠道微生物区系通过作用于肠道树突状细胞来调节中风预后 诱导一种影响T细胞分化的耐受性或促炎表型。这些 中风后肠道免疫变化通过增强的免疫细胞传播到脑和脑膜 贩卖人口。为此，我们将确定(A)不同树突状细胞群体在调节 改变的微生物区系的神经保护作用和(B)微生物区系的细胞和分子靶点 这会导致肠道免疫功能改变，以及它们对中风预后的重要性。这些目标将是 利用小鼠短暂性局灶性脑缺血模型进行组织学和组织学评估 神经学结果，肠道细菌改变的模型，肠道免疫细胞的细胞跟踪，以及体外 免疫细胞共培养模型。这项提议可能会为中风预防开辟新的途径 以及基于肠道微生物群对免疫系统的调节的治疗。

Project Summary/Abstract Stroke is a prevalent and devastating disease with limited therapeutic options. Inflammation and immune cells are major components in the pathophysiology of ischemic stroke and contribute to acute and delayed tissue injury. However, our incomplete understanding of the factors regulating the immune responses triggered by cerebral ischemia remains a significant obstacle to the development of effective therapeutic interventions based on modulating post-ischemic inflammation. Besides activation of brain resident immune cells, ischemic stroke is characterized by the recruitment of peripheral innate and adaptive immune cells that participate in the inflammatory response and contribute to the damage. Commensal microbiota that populate epithelial surfaces play a defining role in shaping the immune system, the development, maintenance and function of which depends critically on the relative abundance and composition of the different microbial species. In particular, intestinal commensal bacteria, the most abundant symbiotic compartment in the body, have emerged as a potent regulator of the immune response to stroke. The long-term goal of this research program is to elucidate the role of intestinal microbiota in stroke pathobiology and develop the experimental framework for new preventative and therapeutic approaches for ischemic stroke. In the present application, we will test the hypothesis that the interaction of commensal intestinal microbiota with dendritic cells is a critical determinant of stroke outcome by modulating the immune system and inflammatory response to cerebral ischemia. Supported by relevant preliminary results, this application will test the hypothesis that commensal intestinal microbiota modulate stroke outcome by acting on intestinal dendritic cells to either induce a tolerogenic or pro-inflammatory phenotype affecting T cell differentiation. These intestinal immune changes propagate to the brain and meninges after stroke by increased immune cell trafficking. To this end, we will determine (a) the roles of different dendritic cell populations in mediating the neuroprotective effects of altered microbiota and (b) the cellular and molecular targets of microbiota that lead to altered intestinal immunity and their importance for stroke outcome. These goals will be achieved using a mouse model of transient focal cerebral ischemia with assessment of histological and neurological outcome, a model of altered gut bacteria, cell tracking of intestinal immune cell, and in vitro immune cell coculture models. This proposal may open the way to new avenues for stroke prevention and therapy based on modulation of the immune system by the gut microbiota.