Integration of mucosal immune responses through the enteric nervous system

描述（由申请方提供）：炎症反应在西方社会的主要死亡原因中起关键致病作用。 缺乏适当的保护性炎症也与感染易感性直接相关，这是发展中国家的一个主要问题。没有什么地方比肠道表面更具有挑战性，因为肠道表面代表了身体暴露于环境的最大表面。人体肠道每天吸收大约80克蛋白质，处理大约1014个细菌。虽然它的大多数微生物以非侵入性肠道为代表，但肠道也是寄生虫、病毒、真菌和致病细菌的目标。毫不奇怪，与肠道相关的免疫系统占体内B和T淋巴细胞的大部分。消化道除了是人体内最大的淋巴器官外，还被认为是“第二个大脑”，其神经元与脊髓一样多。肠神经系统（ENS）在整个肠壁中组织成几个神经丛。粘膜层含有称为粘膜丛的神经网络，其含有潜在地与粘膜免疫细胞接触的神经末梢，尽管这种关联的确切性质有待确定。我们的初步表征表明，抗原呈递细胞（APC）是在肠道固有层内的神经元轴突非常接近。这些轴突向肌间神经丛延伸，在那里它们也被以前未被重视的APC群体包围。该APC群体快速响应来自粘膜区域的病原菌的炎症刺激，甚至在肠壁的更深区域可以发现任何可检测的细菌之前。我们推测，肠神经元可能整合在粘膜表面的一个区域接收的炎症信号，使肠组织为快速反应做好准备，避免系统性侵袭。这些实验的目的是使用复杂的多光子活体显微镜和新的小鼠品系来表征这种相互作用，其中通过遗传标记使这种体内通信可视化。在稳态和肠道感染条件下，APC行为在两个区域中的动力学研究将随后分析改变的神经元活性的功能含义 这些先天免疫细胞的募集和活动。利用我在粘膜免疫学方面的专业知识，结合洛克菲勒大学神经科学家的丰富环境，我希望扩大我们对神经免疫相互作用的功能影响的理解。从这项高度创新的研究中获得的知识将揭示免疫系统和神经系统之间以前未被重视的多向相互作用，增强我们对肠道免疫的理解，为肠道感染和炎症性疾病的替代治疗设计开辟新途径。

DESCRIPTION (provided by applicant): Inflammatory responses play a key pathogenic role in the main causes of mortality in Western societies. Lack of proper protective inflammation is also directly linked to susceptibility to infection, a major concern in developing countries. Nowhere is the balance between protective inflammation against pathogens and tolerance towards innocuous substances more challenging than at the intestinal surface, which represents the largest surface of the body exposed to the environment. The human intestine absorbs roughly 80g of proteins daily and deals with about 1014 bacteria. Although most of its microbes are represented by non- invasive commensals, the intestine is also a target for parasites, viruses, fungi and pathogenic bacteria. Not surprisingly, the immune system associated with the intestine accounts for the majority of B and T lymphocytes in the body. Apart from containing the largest lymphoid organ in the body, the digestive tract is recognized as "a second brain", with as many neurons as the spinal cord. The enteric nervous system (ENS) is organized in several plexuses throughout the intestinal wall. The mucosal layer contains nerve networks known as the mucosal plexus, which contains nerve endings that are potentially in contact with mucosal immune cells, although the exact nature of such associations is to be determined. Our preliminary characterization shows that antigen-presenting cells (APCs) are in close proximity to neuronal axons within the intestinal lamina propria. These axons extend towards the myenteric plexus, where they are also surrounded by a previously unappreciated population of APCs. This population of APCs quickly responds to inflammatory stimuli from pathogenic bacteria from the mucosal region, even before any detectable bacteria can be found at deeper regions of the intestinal wall. We hypothesize that intestinal neurons may integrate inflammatory signals received at one region of the mucosal surface, preparing the intestinal tissue for a quick response, avoiding systemic invasion. The experiments aim to characterize this interaction using a sophisticated multi-photon intravital microscopy and novel mouse strains in which visualization of this communication in vivo is enabled by genetic labeling. The investigation of the dynamics of APC behavior in the two regions at steady state and under intestinal infection conditions will be followed by the analysis of functional implications of altered neuronal activity in the recruitment and activity of these innate immune cells. Using my expertise in mucosal immunology, combined with the rich environment of neuroscientists at the Rockefeller University, I expect to expand our understanding of the functional repercussions of neuroimmune interactions. The knowledge gained from this highly innovative study will shed light on previously unappreciated multidirectional interactions between the immune system and the nervous system, enhancing our comprehension of gut immunity, opening new avenues for the design of alternative treatment for intestinal infections and inflammatory diseases.