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）包括身体最大的环境界面;其免疫系统是 面临着独特的挑战，即保持对饮食和微生物抗原的耐受性， 准备好抵御病原体的入侵协调一致的抵抗和容忍机制有助于防止 病原体传播，限制过度GI损伤，并启动病原体引起的恢复反应 负担或伤害。胃肠道的神经元（肠相关神经元，EAN）与脊髓一样多， 比其他所有隔间加起来都多。EAN包括感觉神经元、中间神经元和 运动神经元，其细胞体在肠内（内在）或肠外（外在），控制各种 在胃肠道内发挥作用。EAN通常被肠道病原体靶向，导致功能性胃肠炎。 病原体清除后的疾病。感染后肠神经元损伤的临床表现包括 未解决的低度肠道炎症、胃肠动力障碍和神经损伤。 然而，感染诱导的神经元损伤的潜在机制是不完全的 明白我们最近的数据表明，鼠肠道感染导致iEAN的快速和持续丧失， 其与包括肠运动障碍的长期胃肠道变化有关。然而，感染 历史和微生物群组成可以分别防止iEAN损失或加速iEAN恢复;研究结果 这可能会导致更好地了解人类感染后IBS和其他疾病相关的 炎症时EAN损伤。成像分析表明，一个亚型特异性神经元的损失， 沙门氏菌感染，转录组学和遗传学方法表明，IEAN细胞死亡机制， 依赖于炎性体途径的成分。肠肌层巨噬细胞耗竭 (MMs)，位于肠神经元附近，以及β2-AR靶向骨髓细胞，导致 增强感染诱导的神经元丢失，表明MM组织保护程序的功能作用 在感染后诱导。我们的观察结果表明，神经元-巨噬细胞相互作用的功能作用， 限制感染诱导的神经元损伤或加速神经元恢复，支持了 这一提议的影响。我们将描述肠道感染后神经细胞死亡的机制 不同的病原体（目标1）。我们还将确定微生物群操作如何挽救神经元死亡 感染后，可能定义特定细菌物种在此过程中的作用（目标2）。最后我们将 研究调节异源性神经元丢失的细胞和分子免疫机制， 继发感染（Aim 3）。通过利用成像，细胞分选-独立的转录组学，单细胞 方法和遗传获得和丧失功能的方法，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。