Integration of mucosal immune responses through the enteric nervous system

描述（由申请人提供）：炎症反应在西方社会死亡的主要原因中起着关键的致病作用。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。肠道是人体暴露在环境中的最大表面，要在对抗病原体的保护性炎症和对无害物质的耐受性之间取得平衡，没有任何地方比肠道表面更具挑战性。人体肠道每天吸收大约80克蛋白质，处理大约1014种细菌。虽然大多数肠道微生物以非侵入性共生生物为代表，但肠道也是寄生虫、病毒、真菌和致病菌的目标。毫不奇怪，与肠道相关的免疫系统占体内B淋巴细胞和T淋巴细胞的大部分。除了拥有人体最大的淋巴器官外，消化道还被认为是“第二大脑”，拥有与脊髓一样多的神经元。肠神经系统（ENS）分布在整个肠壁的几个神经丛中。粘膜层包含被称为粘膜丛的神经网络，其中包含可能与粘膜免疫细胞接触的神经末梢，尽管这种联系的确切性质尚待确定。我们的初步表征表明，抗原呈递细胞（APCs）靠近肠固有层内的神经元轴突。这些轴突向肌丛延伸，在那里它们也被以前未被发现的apc群所包围。这群apc对来自粘膜区域的致病菌的炎症刺激迅速作出反应，甚至在肠壁较深区域发现任何可检测到的细菌之前。我们假设肠道神经元可能整合粘膜表面一个区域接收到的炎症信号，为肠道组织快速反应做好准备，避免全身侵袭。实验旨在利用复杂的多光子活体显微镜和新型小鼠品系来表征这种相互作用，其中通过遗传标记实现了体内这种通信的可视化。在稳态和肠道感染条件下，APC在这两个区域的动态行为将被研究，随后将分析改变的神经元活动的功能意义

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.