Neuroendocrine regulation of intestinal epithelial immunity in C. elegans

项目总结 人类的肠道受到密集的神经支配，而且越来越清楚的是，肠道神经 系统在维持免疫动态平衡方面起着关键作用。然而，理清 单个感觉神经元在调节肠道炎症方面一直具有挑战性，原因是 神经免疫相互作用和肠道微生物群落的显著复杂性。我们 一项令人惊讶的发现，嗅觉受体的发育与先天性免疫调节有关 肠子。从线虫寄主免疫防御调节的正向遗传筛选， 我们发现嗅觉神经元基因olrn-1的功能丧失突变导致了异常免疫。 肠道上皮细胞过度活跃。在线虫发育过程中，olrn-1需要编程 神经元受体在一种特殊类型的感觉神经元--双翼C(AWC)神经元上的表达， 它允许气味辨别和趋化性。在线虫发育过程中，OLRN-1的低活性 在AWC神经元中诱导p38信号以促进嗅觉受体的表达。我们 研究表明，低OLRN-1活性也抑制了p38 PMK-1先天免疫途径。 肠道促进免疫效应物转录，增加肠道病原体的清除，以及 抵抗细菌感染。然而，olrn-1突变体中未经检查的免疫激活对线虫是有毒的。 发育，这是我们的实验室和其他实验室以前展示的一个生理过程，特别是 容易受到肠道免疫动态平衡的干扰。这些数据表明，OLRN-1的表达 线虫中的感觉神经元优化p38PMK-1免疫激活的程度，这是两者必不可少的 应对细菌病原体的挑战，防止不加控制的有害后果 免疫激活。然而，目前尚不清楚AWC感觉神经元中的OLRN-1如何与 P38PMK-1途径在肠道促进免疫动态平衡。 这一提议的中心假设是AWC嗅觉神经元促进免疫稳态 通过神经内分泌介导的抑制肠道p38PMK-1的先天免疫途径。在……里面 支持我们的中心假设，即新免疫调节剂的正向遗传筛查，发现 Olrn-1突变体，也在肠神经肽G蛋白偶联的功能丧失突变等位基因中发现 受体。我们认为该受体和一种同源神经肽激素作用于AWC感觉的下游。 神经元调节线虫的抗病原体反应。这些研究将描述基因的特征 将感觉神经元活动与肠道上皮免疫调节联系起来的机制。我们 预计这些见解将揭示健康免疫控制的祖传策略，并提供基本的 对肠道免疫动态平衡的洞察，可能直接适用于哺乳动物生物学。

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.