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.

项目总结/摘要 伤害感受器神经元是密集地支配胃肠（GI）道的外周感觉神经元， 检测有害/有害刺激以介导包括疼痛的保护性神经反射。肠道也是 到维持体内平衡并保护免受 入侵然而，伤害感受器神经元在调节肠道免疫、屏障保护和宿主免疫中的作用， 防御不太清楚。初步数据显示Trpv 1+亚群的化学发生活化 伤害感受器的释放诱导盲肠和结肠中免疫细胞谱的主要变化，包括T细胞和 巨噬细胞Trpv 1+伤害感受器向脊髓或脑干中的二级神经元发送信号，但 还具有在其外周末端释放神经肽和其它信号分子的能力。 此外，肠从两个解剖学上分离的来源接收伤害感受器输入， 神经节（DRG）神经元以及迷走神经结状神经节（NG）神经元。我之前的数据显示， 大部分支配结肠的脊髓和迷走神经传入都是Trpv 1+，然而，迷走神经和脊髓传入是Trpv 1+。 亚群具有反映跨膜受体聚集的独特转录组模式， 确定感觉形态的通道（例如，pH、温度、机械）。此外，我们的实验室还 先前显示的迷走神经和脊髓伤害感受器通过肽释放调节免疫细胞功能， 肺和小肠。因此，这项建议将测试迷走神经和脊髓的假设， Trpv 1+肠道神经元通过释放TRpv 1+蛋白差异调节先天性和适应性免疫细胞 影响宿主抵抗肠道感染的能力的肽。我会检查是否有脊髓或迷走神经 Trpv 1+神经元参与肠道中的神经免疫相互作用，使用化学遗传学，流式细胞术， 免疫细胞的功能表征（Aim 1）。接下来，我将确定Trpv 1+神经元是否向免疫细胞发出信号， 细胞通过肽使用敲除和拮抗剂的已知介质的神经免疫通讯（目的 2）。最后，我将评估Trpv 1+神经元激活/抑制是否影响宿主对抗肠毒素的能力。 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 trpv 1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 内脏细菌感染治疗靶点的见解。