Integration of Enteric Immune and Nervous Systems in the Mucosal Recall Immune Response

项目总结 胃肠(GI)健康对整体身体健康是必不可少的，但我们对 如何保护胃肠道免受感染。胃肠道高度受神经支配，以协调复杂的生理 与食物摄取、消化和吸收有关的反应。除了食物，胃肠道也是进入人体的地方 微生物和寄生虫，但它受到当地免疫系统的很好保护。进化论的比较 肠道免疫和神经系统的胚胎发育表明，必须有两个系统 他们的共同目标是提供最佳的胃肠道功能表现和保护。 然而，对神经细胞的解剖组织、机制和驱动力知之甚少。 免疫相互作用。我们在这项提案中提出的问题是，为什么以及如何引起肠道紧张和 免疫系统相互调节彼此的功能，以应对感染。 巨噬细胞是进化中最古老的免疫细胞，似乎在与 肠道神经元。我们发现一种特殊类型的肠道巨噬细胞与肠道 神经系统。我们还观察到，胃肠道感染诱导了神经元和粘膜之间的新连接 免疫细胞，如果没有巨噬细胞，这些连接就不能发展。我们假设， 感染期间肠道神经系统的重塑是一个巨噬细胞驱动的过程，这导致 条件性“炎症”反射的新神经免疫途径。通过使用活体成像和转基因 小鼠肠道神经元和巨噬细胞靶向功能的探讨，我们将探索其背后的生物学基础 条件性炎症反射，并研究它们在回忆免疫反应中的作用。

PROJECT SUMMARY Gastrointestinal (GI) health is essential for overall body health, yet many gaps exist in our understanding of how GI tract is protected from infection. The GI tract is highly innervated to coordinate complex physiological responses related to food intake, digestion and absorption. Besides food, the GI tract is the entry site for microbes and parasites, but it is well protected by the local immune system. Comparison of the evolutionary and embryonic development of intestinal immune and nervous systems suggests that two systems must be integrated in their common goal to provide the best functional performance and protection of the GI tract. However, not much is known about the anatomical organization, mechanisms and driving force of neuro- immune interactions. The questions that we ask in this proposal are why and how intestinal nervous and immune systems regulate each other’s functions in response to infection. Macrophages, evolutionary most ancient immunocytes, seem to play a special role in communication with enteric neurons. We found that a specialized type of intestinal macrophages is associated with the enteric nervous system. We also observed that GI infection induces new connections between neurons and mucosal immune cells, and these connections fail to develop if macrophages are absent. We hypothesize, that remodeling of the enteric nervous system during infection is a macrophage-driven process, which results in new neuro-immune pathways of conditional “inflammatory” reflexes. By using intravital imaging and transgenic mouse approach to target functions of intestinal neurons and macrophages, we will explore the biology behind conditional inflammatory reflexes, and examine their role in the recall immune response.