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

项目总结/摘要 中风是一种流行和毁灭性的疾病，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成分， 和延迟的组织损伤。然而，我们对调节免疫的因素的不完全理解， 由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 缺血性中风的特征是外周先天免疫细胞的募集， 适应性免疫细胞参与炎症反应并导致损伤。 占据上皮表面的共生微生物群在塑造免疫系统中起着决定性作用。 系统，其开发、维护和功能关键取决于相对的 不同微生物物种的丰度和组成。尤其是肠粘膜 细菌是体内最丰富的共生区室，已经成为一种有效的调节剂， 对中风的免疫反应这项研究计划的长期目标是阐明 肠道微生物群在中风病理生物学和发展新的实验框架 缺血性中风的预防和治疗方法。在本申请中，我们将测试 这一假说认为，肠道微生物群与树突状细胞的相互作用是一个关键因素， 通过调节免疫系统和炎症反应， 脑缺血在相关初步结果的支持下，本申请将检验该假设 肠道微生物群通过作用于肠道树突状细胞来调节卒中结局， 诱导影响T细胞分化的致耐受性或促炎表型。这些 中风后肠道免疫变化通过增加免疫细胞扩散到大脑和脑膜 贩卖人口为此，我们将确定（a）不同树突状细胞群在介导 改变的微生物群的神经保护作用和（B）微生物群的细胞和分子靶标 导致肠道免疫力改变及其对卒中结局的重要性。这些目标将是 使用短暂性局灶性脑缺血的小鼠模型， 神经学结果，改变的肠道细菌模型，肠道免疫细胞的细胞追踪，以及体外 免疫细胞共培养模型。这一建议可能为预防中风开辟新的途径 以及基于肠道微生物群调节免疫系统的治疗。

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.