Mechanisms of Corneal Neuro-Immune Crosstalk

摘要 神经系统和免疫系统之间复杂的相互作用，作为身体的主要感应器，发挥着 对角膜的动态平衡有重要作用。神经营养分子对神经的维持至关重要。 然而，尽管我们了解了嗜神经分子在脑血管疾病中的影响和多样性 角膜、它们的来源以及调节它们产生的机制仍然难以捉摸。我们的 初步结果表明，某些种类的白细胞，特别是浆细胞样树突状细胞 (PDCs)，可作为神经营养分子的重要来源。因此，在此应用程序中，我们建议 评价各免疫细胞亚群在角膜神经供应中的作用 神经营养分子和Toll样蛋白激活免疫细胞的信号机制 受体(TLR)可以改变它们的神经营养特性。此外，我们的目标是评估在当地收养的 免疫细胞亚群可能促进角膜神经损伤后的神经再生。我们 也旨在确定常驻角膜免疫细胞是否通过耗尽每条角膜神经来调节角膜神经的功能 常住居民角膜白细胞亚群的检测及角膜神经传导功能的检测 电生理学研究以及测量中枢疼痛中心对疼痛刺激的反应 神经系统。接下来，我们打算研究角膜神经(包括感觉神经和自主神经)如何调节。 免疫反应中的几个步骤，从上调黏附分子到增加血管通透性 角膜缘血管与免疫细胞在角膜中的募集及其在角膜内的运动有关。我们建议 研究角膜神经如何影响免疫细胞的多种功能，包括抗原摄取能力 以及对效应细胞的呈递、分泌细胞因子的分布和血管生成分子。应用程序 提出了一种关于角膜神经如何调节免疫的范式转变，并可能引入新的 眼部和全身炎症的免疫调节治疗策略和靶点， 自身免疫、同种异体免疫和传染病。

SUMMARY Complex interactions between the nervous and immune systems, as main sensors of the body, play a significant role in homeostasis of the cornea. Neurotrophic molecules are vital for maintenance of nerves in peripheral tissues, however, despite our understanding on the impact and diversity of neurotropic molecules in the cornea, their sources and the mechanism through which their production is regulated remains elusive. Our preliminary results suggest that certain populations of leukocytes, in particular plasmacytoid dendritic cells (pDCs), can serve as essential source of neurotrophic molecules. Thus, in this application, we propose evaluating the contribution of each subpopulation of immune cells in providing corneal nerves with the neurotrophic molecules and the signaling mechanism through which activation of immune cells through toll like receptors (TLRs) may alter their neurotrophic properties. Further, we aim to assess if local adoptive transfer of subpopulation of immune cells may enhance nerve regeneration following nerve damage in the cornea. We also aim to determine if resident corneal immune cells regulate function of corneal nerves by depleting each subpopulation of the resident corneal leukocyte and assessing electrical conduction of corneal nerves via electrophysiological studies as well as measuring the response to painful stimuli in the pain centers in central nervous system. Next, we propose to study how corneal nerves (both sensory and autonomic) may regulate several steps in immune reaction, from up-regulation of adhesion molecules and increasing the permeability of limbal vessels to recruitment of immune cells to the cornea and their intra-corneal locomotion. We suggest studying how corneal nerves shape multiple functions of immune cells, including capacity of antigen uptake and presentation to effector cells, profile of secretory cytokines, and angiogenic molecules. The application proposes a paradigm shift on how corneal nerves may mediate immunity, and would potentially introduce new immunomodulatory therapeutic strategies and targets for ocular as well as systemic inflammatory, autoimmune, alloimmune and infectious diseases.