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.

项目摘要/摘要 伤害性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/有害刺激以调节包括疼痛在内的保护性神经反射。肠子也是常驻的 不同群体的先天和适应性免疫细胞，维持体内平衡并保护 入侵。然而，伤害性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 辩护没有得到很好的理解。初步数据显示，TRPV1+亚群的化学生成激活 伤害性感受器的变化导致盲肠和结肠免疫细胞图谱的重大变化，包括T细胞和 巨噬细胞。TRPV1+伤害性感受器向脊髓或脑干的二级神经元发送信号，但 也有能力在其外周终端释放神经肽和其他信号分子。 此外，肠道接受来自两个解剖学上不同来源的伤害性感受器输入，脊髓背根 神经节(DRG)神经元和迷走神经节(NG)神经元。我之前的数据显示， 支配结肠的脊髓和迷走神经传入的很大一部分是TRPV1+，然而迷走神经和脊髓的传入 亚群有独特的转录模式，反映了跨膜受体和 决定感觉模式的通道(例如，pH、温度、机械)。另外，我们的实验室有 先前显示迷走神经和脊髓伤害性感受器通过在脑组织中释放多肽来调节免疫细胞功能 肺和小肠分别为。因此，这一提议将检验迷走神经和脊髓 TRPV1+肠神经支配神经元对天然免疫细胞和获得性免疫细胞的不同调节作用 影响宿主抵抗肠道感染能力的多肽。我会调查是脊椎还是迷走神经 利用化学遗传学、流式细胞术和免疫组织化学技术，TRPV1+神经元参与肠道的神经免疫相互作用 免疫细胞的功能特征(Aim1)。接下来，我将确定TRPV1+神经元是否发出免疫信号 使用已知神经免疫通讯介体的敲除和拮抗剂的多肽(目的 2)。最后，我将评估TRPV1+神经元的激活/抑制是否影响宿主对抗肠道病毒的能力 感染，特别是轮状柠檬酸杆菌(目标3)。这项提案的结果将阐明 TRPV1伤害性感受器在稳态和肠道感染后对免疫细胞的调节作用这可能会提供新的 洞察内脏细菌感染的治疗靶点。