Neuroendocrine regulation of intestinal epithelial immunity in C. elegans

项目摘要 人的肠是密集神经支配的，并且变得越来越清楚的是，肠神经系统是由肠神经系统支配的。 系统在维持免疫稳态中起着关键作用。然而，要理清 单个感觉神经元在肠道炎症调节中的作用一直是具有挑战性的，这是由于 神经免疫相互作用和肠道微生物群落的显著复杂性。我们 令人惊讶的发现，嗅觉受体的发育与先天免疫调节有关， 肠子通过对线虫中宿主免疫防御调节因子的正向遗传筛选，优雅， 我们发现嗅觉神经元基因olrn-1的功能缺失突变导致异常的免疫反应， 肠上皮细胞过度活化。在线虫的发育过程中，olrn-1被要求对 在一种特殊类型的感觉神经元，两栖翼C（AWC）神经元中神经元受体的表达， 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 诱导AWC神经元自身内的p38信号传导以促进嗅觉受体表达。我们 表明低OLRN-1活性也可以在免疫系统中去抑制p38 PMK-1先天免疫途径。 肠以促进免疫效应物转录，增加肠道病原体的清除，和 抵抗细菌感染。然而，在OLRN-1突变体中未经抑制的免疫激活对线虫是有毒的 发育，我们的实验室和其他人以前已经证明的生理过程，特别是 易受肠道免疫平衡紊乱的影响这些数据表明OLRN-1表达 C.感觉神经元elegans优化了p38 PMK-1免疫激活的程度，这对于 应对来自细菌病原体的挑战，并防止未经检查的 免疫激活然而，目前尚不清楚AWC感觉神经元中的OLRN-1是如何与神经元进行通信的。 肠道中的p38 PMK-1途径促进免疫稳态。 这个提议的中心假设是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，即新免疫调节因子的正向遗传筛选， olrn-1突变体，还确定了肠神经肽G蛋白偶联的功能丧失突变等位基因， 受体的我们认为，这种受体和同源神经肽激素的行为下游的AWC感觉 神经元调节C.优雅这些研究将描述遗传 将感觉神经元活动与肠上皮免疫调节联系起来的机制。我们 我希望这些见解将揭示健康免疫控制的祖先策略，并提供基本的 对肠道免疫稳态的见解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.