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

树突状细胞在调节缺血性中风肠脑免疫轴中的作用

• 批准号: 10680797
• 负责人: Josef Anrather
• 金额: $ 47.03万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680797
• 关键词: Acute; Affect; Biological Response Modifiers; Brain; Brain Injuries; Brain Ischemia; CD4 Positive T Lymphocytes; Cause of Death; Cells; Cerebral Ischemia; Clinical Trials; Coculture Techniques; Dendritic Cells; Development; Dietary Intervention; Disease; Epithelium; Equilibrium; Functional disorder; Goals; Histologic; Human; ITGAX gene; Immune; Immune response; Immune system; Immunity; Immunosuppression; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin 6 Receptor; Interleukin-6; Interphase; Intestinal Content; Intestines; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Lymphocyte; Maintenance; Mediating; Mediator; Meninges; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Natural Immunity; Neurological outcome; Pathologic Processes; Pathology; Pathway interactions; Peripheral; Phenotype; Play; Population; Probiotics; Regulatory T-Lymphocyte; Reporter; Research; Rodent; Role; Route; Shapes; Signal Pathway; Signal Transduction; Small Intestines; Stroke; Stroke prevention; Surface; T cell differentiation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; adaptive immunity; brain cell; cellular targeting; cerebral ischemic injury; commensal bacteria; commensal microbes; disability; gut bacteria; gut microbes; gut microbiota; immune cell infiltrate; immunological status; immunoregulation; in vivo Model; infection risk; ischemic injury; lymphoid organ; microbial; microbial composition; microbiome; microbiota; microbiota-gut-brain axis; mouse model; neuroprotection; novel strategies; post stroke; programs; receptor; recruit; repaired; stroke outcome; stroke patient; stroke risk; stroke therapy; success; targeted treatment; therapeutically effective; tissue injury; trafficking; transmission process; γδ T cells

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.

项目摘要/摘要 中风是一种普遍的毁灭性疾病，治疗选择有限。发炎和 免疫细胞是缺血性中风病理生理学中的主要成分，并导致急性 并延迟组织损伤。但是，我们对调节免疫的因素的不完全理解 脑缺血引起的反应仍然是发展有效的重要障碍 基于调节缺血后炎症的治疗干预措施。除了大脑激活 常驻免疫细胞，缺血性中风的特征是募集外周种先天和 参与炎症反应并导致损害的自适应免疫细胞。 填充上皮表面的共生微生物群在塑造免疫方面起着决定性的作用 系统，开发，维护和功能严重取决于相对 不同微生物物种的丰度和组成。特别是肠内 细菌是体内最丰富的共生室，已成为有效的调节剂 对中风的免疫反应。该研究计划的长期目标是阐明 中风病理学中的肠道菌群，并开发了新的实验框架 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群与树突状细胞的相互作用是关键 通过调节免疫系统和对 脑缺血。在相关初步结果的支持下，此应用将检验假设 通过在肠道树突状细胞上作用到 诱导影响T细胞分化的耐受性或促炎的表型。这些 肠道免疫变化会通过增加的免疫细胞在中风后传播到大脑和脑膜 贩运。为此，我们将确定（a）不同树突细胞种群介导的作用 菌群改变的神经保护作用和（b）菌群的细胞和分子靶标的神经保护作用 这导致肠道免疫力改变及其对中风结果的重要性。这些目标将是 使用组织学和组织学和 神经系统结果，一种改变的肠道细菌，肠道免疫细胞的细胞跟踪和体外 免疫细胞共培养模型。该提议可能为预防中风的新途径开辟道路 和基于肠道菌群对免疫系统的调节的治疗。