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 伤害感受器神经元是周围的感觉神经元，可密度支配胃肠道（GI）的神经元， 检测有害/有害刺激以介导保护性神经反射，包括疼痛。肠道也是居民 对于维持体内平衡并预防的不同先天和适应性免疫细胞的多种多样 入侵。但是，伤害感受器神经元在调节肠道免疫学，屏障保护和宿主中的作用 国防并不理解。初步数据表明，TRPV1+亚群的化学发生激活 伤害感受器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+伤害感受器将信号发送到脊髓或脑干中的二阶神经元，但 还具有在其周围末端释放神经肽和其他信号分子的能力。 此外，肠道从两个解剖学分开的来源（脊柱背根）接收伤害感受器输入 神经节神经元以及迷走神经神经元（NG）神经元。我以前的数据表明 结肠支配的脊柱和迷走神经传入中的很大一部分是TRPV1+，但是迷走神经和脊柱 亚群具有独特的转录组模式，反映了跨膜受体的聚类和 确定感觉方式的通道（例如pH，温度，机械）。此外，我们的实验室有 先前显示的迷走神经和脊柱伤害感受器通过肽在 肺和小肠。因此，该建议将检验迷走神经和脊柱的假设 TRPV1+肠内神经元通过释放来差异地调节先天和适应性免疫细胞 影响宿主对抗肠道感染的能力的肽。我会调查脊柱还是迷走神经 TRPV1+神经元使用化学遗传学，流式细胞术和 免疫细胞的功能表征（AIM1）。接下来，我将确定TRPV1+神经元是否信号为免疫 使用肽和拮抗剂通过肽和已知神经免疫传播的介体的拮抗剂（目标） 2）。最后，我将评估TRPV1+神经元激活/抑制是否会影响宿主对抗肠的能力 感染，特别是柠檬酸啮齿动物（AIM 3）。该提案的结果将阐明 TRPV1伤害感受器在稳态和肠感染后调节免疫细胞。这可能会提供新的 对内脏细菌感染的治疗靶点的见解。