Neuroendocrine regulation of intestinal epithelial immunity in C. elegans

线虫肠上皮免疫的神经内分泌调节

• 批准号: 10284662
• 负责人: Read Pukkila-Worley
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284662
• 关键词: Address; Afferent Neurons; Alleles; Bacterial Infections; Biological Response Modifiers; Biology; Caenorhabditis elegans; Cell Line; Chemotaxis; Communication; Data; Development; Discrimination; Disease; Enteric Nervous System; Epithelial; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Screening; Genetic Transcription; Gonadotropin-Releasing Hormone Receptor; Health; Homeostasis; Homologous Gene; Hormone Receptor; Hormones; Host Defense; Human; Immune; Immune response; Immunity; Individual; Inflammation; Inflammatory Response; Intestines; Knowledge; Laboratories; Lead; Left; Link; Mediating; Nematoda; Neurons; Neuropeptide Gene; Neuropeptides; Neurosecretory Systems; Odors; Pathway interactions; Physiological Processes; Play; Regulation; Signal Transduction; Specificity; Testing; Tissues; Wing; bacterial resistance; disabling symptom; enteric pathogen; expectation; immune activation; immunoregulation; inflammatory disease of the intestine; innate immune pathways; insight; intestinal epithelium; loss of function; loss of function mutation; microbial; microbial community; microorganism; mutant; new therapeutic target; novel; olfactory receptor; p38 Mitogen Activated Protein Kinase; pathogen; pathogenic bacteria; prevent; programs; receptor; receptor expression; relating to nervous system; response; Address; Afferent Neurons; Alleles; Bacterial Infections; Biological Response Modifiers; Biology; Caenorhabditis elegans; Cell Line; Chemotaxis; Communication; Data; Development; Discrimination; Disease; Enteric Nervous System; Epithelial; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Screening; Genetic Transcription; Gonadotropin-Releasing Hormone Receptor; Health; Homeostasis; Homologous Gene; Hormone Receptor; Hormones; Host Defense; Human; Immune; Immune response; Immunity; Individual; Inflammation; Inflammatory Response; Intestines; Knowledge; Laboratories; Lead; Left; Link; Mediating; Nematoda; Neurons; Neuropeptide Gene; Neuropeptides; Neurosecretory Systems; Odors; Pathway interactions; Physiological Processes; Play; Regulation; Signal Transduction; Specificity; Testing; Tissues; Wing; bacterial resistance; disabling symptom; enteric pathogen; expectation; immune activation; immunoregulation; inflammatory disease of the intestine; innate immune pathways; insight; intestinal epithelium; loss of function; loss of function mutation; microbial; microbial community; microorganism; mutant; new therapeutic target; novel; olfactory receptor; p38 Mitogen Activated Protein Kinase; pathogen; pathogenic bacteria; prevent; programs; receptor; receptor expression; relating to nervous system; response

PROJECT SUMMARY The human intestine is densely innervated, and it is becoming increasingly clear that the enteric nervous system plays a key role in maintaining immune homeostasis. However, disentangling the contribution of individual sensory neurons in the regulation of intestinal inflammation has been challenging, owing to the marked complexity of both neural-immune interactions and the microbial communities in the intestine. We made a surprising discovery that olfactory receptor development is linked to innate immune regulation in the intestine. From a forward genetic screen for regulators of host immune defenses in the nematode C. elegans, we found that loss-of-function mutations in the olfactory neuron gene olrn-1 caused aberrant immune hyperactivation in the intestinal epithelium. During nematode development, olrn-1 is required to program the expression of neuronal receptors in one particular type of sensory neuron, the amphid wing C (AWC) neurons, which allows odor discrimination and chemotaxis. During nematode development, low activity of OLRN-1 induces p38 signaling within AWC neurons themselves to promote olfactory receptor expression. We demonstrated that low OLRN-1 activity also de-represses the p38 PMK-1 innate immune pathway in the intestine to promote immune effector transcription, increased clearance of an intestinal pathogen, and resistance to bacterial infection. However, unchecked immune activation in olrn-1 mutants is toxic to nematode development, a physiological process that our laboratory, and others, have previously shown is particularly vulnerable to perturbations in intestinal immune homeostasis. These data suggest that OLRN-1-expressing sensory neurons in C. elegans optimize the degree of p38 PMK-1 immune activation, which is essential both to handle challenges from bacterial pathogens and to prevent the deleterious consequences of unchecked immune activation. However, it is not known how OLRN-1 in AWC sensory neurons communicates with the p38 PMK-1 pathway in the intestine to promote immune homeostasis. The central hypothesis of this proposal is that AWC olfactory neurons promote immune homeostasis through the neuroendocrine-mediated suppression of the intestinal p38 PMK-1 innate immune pathway. In support of our central hypothesis, the forward genetic screen for novel immune regulators, which uncovered olrn-1 mutants, also identified a loss-of-function mutant allele in an intestinal neuropeptide G protein-coupled receptor. We propose that this receptor and a cognate neuropeptide hormone act downstream of AWC sensory neurons to regulate anti-pathogen responses in C. elegans. These studies will characterize the genetic mechanisms that link sensory neuron activity to the regulation of immunity in the intestinal epithelium. We expect that these insights will reveal ancestral strategies of healthy immune control and provide fundamental insights into intestinal immune homeostasis that may be directly applicable to mammalian biology.

项目摘要 人类的肠道密集于神经，越来越清楚肠子紧张 系统在维持免疫稳态方面起着关键作用。但是，解开 肠炎调节中的个体感觉神经元由于 神经免疫相互作用和肠道中的微生物群落的复杂性。我们 令人惊讶的发现，嗅觉受体的发展与先天免疫调节有关 肠。从线虫秀丽隐杆线虫中宿主免疫防御的调节剂的正向遗传筛选中， 我们发现嗅觉神经元基因OLRN-1中的功能丧失突变引起异常免疫 肠上皮过度激活。在线虫开发过程中，需要OLRN-1来编程 神经元受体在一种特定类型的感觉神经元中的表达，两栖翼C（AWC）神经元， 这允许气味歧视和趋化性。在线虫发展过程中，OLRN-1活性低 在AWC神经元本身中诱导p38信号传导，以促进嗅觉受体表达。我们 证明较低的OLRN-1活性还可以驱除p38 pmk-1先天免疫途径 肠道以促进免疫效应子转录，增加肠道病原体的清除率，以及 对细菌感染的抗性。但是，OLRN-1突变体中未检查的免疫激活对线虫有毒 开发，我们的实验室和其他人以前表明的生理过程特别是 容易受到肠道免疫稳态的扰动。这些数据表明OLRN-1表达 秀丽隐杆线虫中的感觉神经元优化了p38 pmk-1免疫激活的程度，这对 应对细菌病原体的挑战，以防止不受组织的有害后果 免疫激活。但是，尚不知道AWC感觉神经元中的OLRN-1如何与 肠道中的P38 PMK-1途径可促进免疫稳态。 该提议的中心假设是AWC嗅觉神经元促进免疫稳态 通过神经内分泌介导的肠道p38 pmk-1先天免疫途径的抑制。在 支持我们的中心假设，即新型免疫调节剂的正向遗传筛选 OLRN-1突变体，还鉴定出在肠道神经肽G蛋白偶联的功能丧失突变体等位基因 受体。我们建议该受体和同源神经肽激素在AWC感觉的下游作用 神经元调节秀丽隐杆线虫中的抗病原体反应。这些研究将表征遗传 将感觉神经元活性与肠上皮中免疫的调节的机制。我们 预计这些见解将揭示健康免疫控制的祖先策略并提供基本 对可能直接适用于哺乳动物生物学的肠道免疫稳态的见解。