Neuro-immune interactions at the intestinal surface

肠道表面的神经免疫相互作用

• 批准号: 10203960
• 负责人: Daniel S Mucida
• 金额: $ 51.95万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203960
• 关键词: Afferent Neurons; Bacterial Gastroenteritis; Bacterial Infections; Body Surface; Cell Death; Cell Separation; Cells; Central Nervous System Diseases; Clinical; Cues; Data; Disease; Enteral; Environment; Exposure to; Functional Gastrointestinal Disorders; Gastrointestinal Motility; Gastrointestinal tract structure; Gene Expression; Genetic; Human; Image; Immune; Immune system; Impairment; Infection; Inflammasome; Inflammation; Inflammatory Bowel Diseases; Injury; Interneurons; Interstitial Cell of Cajal; Intestines; Irritable Bowel Syndrome; Lead; Maintenance; Modeling; Molecular; Motor Neurons; Mus; Myeloid Cells; Myenteric Plexus; Nervous system structure; Neuroglia; Neuroimmune; Neurons; Pathogenicity; Pathology; Pathway interactions; Peristalsis; Physiological Processes; Play; Population; Prevention; Process; Recording of previous events; Recovery; Reporting; Resistance; Role; Salmonella infections; Signal Transduction; Spinal Cord; Surface; Tissues; base; beta-2 Adrenergic Receptors; dietary; enteric infection; enteric pathogen; gastrointestinal; genetic approach; gut microbiota; helminth infection; inflammatory disease of the intestine; loss of function; macrophage; microbial; microbiome; microbiota; microorganism antigen; motility disorder; nerve damage; nervous system disorder; neuroinflammation; neuron loss; pathogen; prevent; programs; response; secondary infection; transcriptomics

Project Summary The gastrointestinal (GI) tract comprises the largest environmental interface of the body; its immune system is posed with the unique challenge of maintaining tolerance to dietary and microbial antigens while remaining poised to protect against pathogen invasion. Coordinated resistance and tolerance mechanisms serve to prevent pathogenic dissemination, limit excessive GI damage, and initiate recovery responses induced by pathogenic burden or injury. The GI tract hosts as many neurons (enteric-associated neurons, EANs) as the spinal cord and more immune cells than all other compartments together. EANs include sensory neurons, interneurons, and motor neurons with cell bodies within (intrinsic) or outside the intestine (extrinsic), which control a variety of functions within the GI tract. EANs are often targeted by enteric pathogens, resulting in functional gastrointestinal disorders post pathogen clearance. The clinical presentations of post-infectious enteric neuronal damage include unresolved low-grade intestinal inflammation, gastrointestinal motility impairment, and nerve damage. Nevertheless, the underlying mechanisms involved in infection–induced neuronal damage are incompletely understood. Our recent data indicates that murine enteric infection results in a rapid and persistent loss of iEANs, which is associated with prolonged gastrointestinal changes including intestinal dysmotility. However, infection history and microbiota composition can prevent iEAN loss or accelerate iEAN recovery, respectively; findings that may lead to a better understanding of human post-infectious IBS and additional disorders associated with EAN damage during inflammation. Imaging analyses suggested a subtype–specific neuronal loss upon Salmonella infection, and transcriptomics and genetic approaches indicated an iEAN cell death mechanism that is dependent on components of the inflammasome pathway. Depletion of intestinal muscularis macrophages (MMs), located in close proximity to enteric neurons, as well as targeting of β2-AR on myeloid cells, resulted in enhanced infection-induced neuronal loss, suggesting a functional role for a MM tissue protective program induced upon infection. Our observations suggest a functional role for neuron–macrophage interactions in limiting infection-induced neuronal damage or accelerating neuronal recovery, supporting the significance and impact of this proposal. We will characterize mechanisms underlying neuronal cell death post enteric infection with different pathogens (Aim 1). We will also to define how microbiota manipulations can rescue neuronal death post infection, possibly defining a role for specific bacterial species in this process (Aim 2). Finally, we will investigate the cellular and molecular immune mechanisms regulating neuronal loss during heterologous secondary infections (Aim3). By utilizing imaging, cell sorting–independent transcriptomics, single-cell approaches and genetic gain– and loss–of-function approaches, this proposal aims to characterize cellular and molecular components of neuro-immune crosstalk following enteric infections.

项目摘要 胃肠道（GI）构成人体最大的环境界面；它的免疫系统是 在保持饮食和微生物抗原的耐受性的同时，面临着独特的挑战 准备防止病原体入侵。协调的抵抗力和耐受性机制有助于防止 致病性传播，限制过多的胃肠道损伤并启动致病性引起的恢复反应 负担或受伤。胃肠道具有与脊髓一样多的神经元（肠相关神经元）和 与所有其他隔室相比，免疫细胞更多。 EAN包括感觉神经元，中间神经元和 运动神经元，内部（内在）或肠道内部（外部），该神经元控制多种多样 胃肠道中的功能。 EAN通常由肠道病原体靶向，导致功能性胃肠道 病原体清除后疾病。感染后肠神经元损害的临床表现包括 未解决的低度肠道感染，胃肠道运动障碍和神经损伤。 然而，感染引起的神经元损害涉及的基本机制并不完全 理解。我们最近的数据表明，鼠类启动子感染导致IEAN迅速而持续的损失， 这与长时间的胃肠道变化有关，包括肠道运动障碍。但是，感染 病史和微生物群的组成可以分别防止IEAN损失或加速IEAN恢复；发现 这可能会导致对人类感染后的IB和与其他疾病有关的更好理解 EAN炎症期间的损害。影像学分析表明，亚型 - 特异性神经元丧失 沙门氏菌感染以及转录组学和遗传方法表明一种IEAN细胞死亡机制 取决于炎性途径的组件。肠道巨噬细胞的消耗 （MMS），位于接近进入神经元的近端，以及在髓样细胞上靶向β2-AR的靶向 增强感染引起的神经元丧失，表明MM组织保护程序的功能作用 感染后诱导。我们的观察表明，神经元 - 巨噬细胞相互作用的功能作用 限制感染引起的神经元损伤或加速神经元恢复，支持显着性和 我们将表征神经元细胞死亡后的机制促进感染 与不同的病原体（AIM 1）。我们还将定义微生物群如何挽救神经元死亡 感染后，可能在此过程中定义了特定细菌物种的作用（AIM 2）。最后，我们会的 研究在异源过程中应对神经元丧失的细胞和分子免疫机制 继发感染（AIM3）。通过使用成像，单细胞排序独立的转录组学，单细胞 方法和遗传增益和功能障碍方法，该建议旨在表征细胞和 肠道感染后神经免疫串扰的分子成分。