Trpv1 nociceptor neurons modulate immune cells to regulate intestinal immunity in enteric infection

Trpv1伤害感受器神经元调节免疫细胞以调节肠道感染中的肠道免疫

• 批准号: 10749782
• 负责人: Kimberly A Meerschaert
• 金额: $ 6.95万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749782
• 关键词: Afferent Neurons; Anatomy; Bacteria; Bacterial Infections; Body Weight decreased; Brain Stem; Breeding; Calcitonin Gene-Related Peptide; Cecum; Cell physiology; Cells; Citrobacter rodentium; Coculture Techniques; Colon; Communication; Data; Designer Drugs; Enteral; Flow Cytometry; Gastrointestinal tract structure; Genetic; Homeostasis; Host Defense; Immune; Immunity; Immunology; In Vitro; Infection; Intestines; Invaded; Knock-out; Knockout Mice; Laboratories; Ligands; Location; Lung; Macrophage; Mechanics; Mediating; Mediator; Membrane; Modality; Monitor; Mus; Neuroimmune; Neurons; Neuropeptides; Nociceptors; Nodose Ganglion; Pain; Pattern; Peptides; Peripheral; Phenotype; Population Heterogeneity; Predisposition; Protocols documentation; Reflex action; Role; Sensory; Signal Transduction; Signaling Molecule; Small Intestines; Source; Spinal; Spinal Cord; Spinal Ganglia; Stimulus; T-Lymphocyte; Temperature; Testing; Vasoactive Intestinal Peptide; Vertebral column; Virus; Visceral; antagonist; enteric infection; experimental study; fighting; gastrointestinal; immunoregulation; in vivo; insight; loss of function; neural; neurotransmission; receptor; therapeutic target; transcriptomics

PROJECT SUMMARY/ABSTRACT Nociceptor neurons are peripheral sensory neurons that densely innervate the gastrointestinal (GI) tract, detecting noxious/harmful stimuli to mediate protective neural reflexes including pain. The gut is also resident to a diverse population of innate and adaptive immune cells that maintain homeostasis and protect against invasion. However, the role of nociceptor neurons in regulating gut immunology, barrier protection, and host defense is not well understood. Preliminary data shows that chemogenetic activation of Trpv1+ subpopulation of nociceptors induces major changes in the immune cell profile in the cecum and colon, including T cells and macrophages. Trpv1+ nociceptors send signals to second order neurons in the spinal cord or brainstem, but also have the ability to release neuropeptides and other signaling molecules at their peripheral terminals. Furthermore, the gut receives nociceptor input from two anatomically separate sources, spinal dorsal root ganglia (DRG) neurons as well as vagal nodose ganglia (NG) neurons. My previous data has shown that a large proportion of both spinal and vagal afferents innervating the colon are Trpv1+, however, vagal and spinal subpopulations have unique transcriptomic patterns that reflect clustering of transmembrane receptors and channels that determine sensory modalities (e.g., pH, temperature, mechanical). In addition, our laboratory has previously shown vagal and spinal nociceptors to modulate immune cell function through peptide release in the lungs and small intestine, respectively. Therefore, this proposal will test the hypothesis that vagal and spinal Trpv1+ gut-innervating neurons differentially modulate innate and adaptive immune cells through release of peptides which impacts the ability of the host to fight enteric infections. I will investigate if spinal or vagal Trpv1+ neurons are involved in neuroimmune interactions in the gut using chemogenetics, flow cytometry, and functional characterization of immune cells (Aim1). Next, I will determine if Trpv1+ neurons signal to immune cells via peptides using knockout and antagonists of known mediators of neuroimmune communication (Aim 2). Finally, I will assess if Trpv1+ neuronal activation/inhibition impacts the ability of the host to fight enteric infections, specifically Citrobacter rodentium (Aim 3). The results from this proposal will elucidate the role of Trpv1 nociceptors in modulating immune cells at steady state and after enteric infection. This may provide new insight for therapeutic targets of visceral bacterial infections.

项目概要/摘要 伤害感受器神经元是密集支配胃肠道的外周感觉神经元， 检测有害/有害刺激以介导包括疼痛在内的保护性神经反射。肠道也是常驻的 多种先天性和适应性免疫细胞，可维持体内平衡并防止 入侵。然而，伤害感受器神经元在调节肠道免疫、屏障保护和宿主方面的作用 防守不太了解。初步数据表明，Trpv1+ 亚群的化学遗传学激活 伤害感受器的数量会引起盲肠和结肠中免疫细胞谱的重大变化，包括 T 细胞和 巨噬细胞。 Trpv1+ 伤害感受器向脊髓或脑干中的二级神经元发送信号，但是 还具有在其外周末端释放神经肽和其他信号分子的能力。 此外，肠道从两个解剖学上独立的来源接收伤害感受器输入，即脊髓背根 神经节（DRG）神经元以及迷走神经结节神经节（NG）神经元。我之前的数据表明 支配结肠的脊髓和迷走神经传入神经的很大一部分是 Trpv1+，然而，迷走神经和脊髓传入神经 亚群具有独特的转录组模式，反映跨膜受体的聚集 决定感官模式（例如 pH、温度、机械）的通道。此外，我们实验室还有 先前表明迷走神经和脊髓伤害感受器通过肽释放来调节免疫细胞功能 分别是肺和小肠。因此，该提案将检验迷走神经和脊髓的假设 Trpv1+ 肠道神经元通过释放 影响宿主抵抗肠道感染能力的肽。我会检查是脊髓还是迷走神经 Trpv1+ 神经元利用化学遗传学、流式细胞术和免疫学方法参与肠道中的神经免疫相互作用。 免疫细胞的功能表征（目标1）。接下来，我将确定 Trpv1+ 神经元是否向免疫发出信号 使用已知的神经免疫通讯介质的敲除和拮抗剂通过肽对细胞进行研究（目的 2）。最后，我将评估 Trpv1+ 神经元激活/抑制是否影响宿主对抗肠道的能力 感染，特别是啮齿类柠檬酸杆菌（目标 3）。该提案的结果将阐明 Trpv1 伤害感受器在稳态和肠道感染后调节免疫细胞。这可能会提供新的 洞察内脏细菌感染的治疗靶点。