Mechanisms of Corneal Neuro-Immune Crosstalk

总结 神经系统和免疫系统作为人体的主要传感器，它们之间的复杂相互作用， 在角膜的稳态中起重要作用。神经营养分子对于维持神经系统的功能至关重要。 然而，尽管我们了解了外周组织中亲神经分子的影响和多样性， 角膜、它们的来源和调节它们产生的机制仍然是难以捉摸的。我们 初步结果表明，某些白细胞群体，特别是浆细胞样树突状细胞， pDC（pDCs）可以作为神经营养分子的必需来源。因此，在本申请中，我们提出 评价每种免疫细胞亚群在为角膜神经提供免疫刺激中的作用， 神经营养分子和信号传导机制，通过该机制，免疫细胞通过Toll样激活 受体（TLR）可以改变它们的神经营养特性。此外，我们的目标是评估当地的收养转移， 免疫细胞亚群可以增强角膜神经损伤后的神经再生。我们 还旨在确定是否常驻角膜免疫细胞调节角膜神经的功能， 常驻角膜白细胞的亚群和评估角膜神经的电传导， 电生理学研究以及测量中枢疼痛中枢对疼痛刺激的反应， 神经系统接下来，我们建议研究角膜神经（感觉神经和自主神经）如何调节 免疫反应的几个步骤，从上调粘附分子和增加渗透性， 角膜缘血管对免疫细胞向角膜的募集及其在角膜内的运动的影响。我们建议 研究角膜神经如何塑造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、分泌性细胞因子和血管生成分子的概况。应用 提出了一个关于角膜神经如何介导免疫的范式转变，并可能引入新的 免疫调节治疗策略和眼部以及全身炎症的靶标， 自身免疫性、同种免疫性和感染性疾病。

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.