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/文摘