Role of plasmacytoid dendritic cells in corneal nerve health and regeneration

 描述(申请人提供)：角膜神经功能障碍是许多眼表疾病的病理生理基础，会导致相当大的发病率，包括神经营养性角膜炎和干眼病，因此角膜神经健康是维持视力的先决条件。尽管传统观点认为免疫细胞对神经再生有害，但最近的证据表明，免疫细胞在神经元再生中可以显示出有益的效果。例如，巨噬细胞和传统的树突状细胞在为神经损伤后的神经再生提供神经保护和神经营养的微环境方面发挥了关键作用。尽管最近有证据表明免疫细胞具有神经保护和神经再生功能，但内源性神经营养分子在角膜中的作用和来源仍然难以捉摸。此外，最近发现的浆细胞样树突状细胞(PDCs)的影响仍有待确定，pDC是一种重要的免疫细胞亚群，位于角膜基底层神经丛下方的前基质中。这些细胞协调和连接先天和获得性免疫反应，并参与诱导对移植组织或肿瘤的耐受。我们的初步结果表明，PDCs在维持和发挥角膜神经功能中起着至关重要的作用，因为我们证明了角膜中PDCs的局部枯竭会导致突然而严重的神经丢失和角膜感觉的减弱。我们的假设是，PDCs通过分泌神经营养分子来促进神经的维持、功能和再生。我们的具体目标包括评估PDCs对角膜神经维护和健康的意义，以及研究PDCs对神经损伤后角膜神经再生的影响。我们对PDCs如何参与调节角膜神经微环境的新观点有望扩大我们对角膜神经纤维和免疫细胞之间的串扰以及这种串扰对角膜神经健康和功能的影响的知识，远远超出目前的状态。此外，这一应用为评估角膜PDCs在神经保护和再生中的意义提供了活体方法。因此，这一建议将阐明pDC的神经保护和神经再生特性，可能导致新的治疗方法，并可能适用于角膜以外的组织和神经再生至关重要的情况，包括创伤性神经系统损伤、神经退行性疾病和周围神经疾病。

 DESCRIPTION (provided by applicant): Corneal nerve dysfunction is the pathophysiologic basis of many ocular surface diseases, causing considerable morbidity, including neurotrophic keratitis and dry eye disease and therefore corneal nerve health is a prerequisite for the maintenance of vision. Despite the traditional point of view that immune cells are deleterious for nerve regeneration, recent evidence suggests that immune cells can show beneficial effects in neuronal regeneration. For instance, macrophages and conventional dendritic cells are among the key players in providing a neuro-protective and neuro-trophic microenvironment for nerve regeneration following nerve damage. Despite recent evidence on neuro-protective and neuro-regenerative functions of immune cells, the role and source of endogenous neurotrophic molecules in the cornea remains elusive. Moreover, the impact of recently identified plasmacytoid dendritic cells (pDCs), a vital subset of immune cells that reside in the anterior stroma just beneath sub-basal corneal nerve plexus of cornea, remains to be determined. These cells orchestrate and link innate and adaptive immune responses and are implicated in the induction of tolerance to transplanted tissues or tumors. Our preliminary results suggest that pDCs are vital in the maintenance and function of corneal nerves, as we demonstrate that local depletion of pDCs in the cornea leads to abrupt and severe nerve loss and diminishment of corneal sensation. Our hypothesis is that pDCs contribute to maintenance, function, and regeneration of nerves through secretion of neurotrophic molecules. Our specific aims include evaluating the significance of pDCs on corneal nerve maintenance and health as well as studying the impact of pDCs on neural regeneration in the cornea following nerve damage. Our fresh perspective on how pDCs contribute to regulation of corneal nerve microenvironment holds promise of amplifying our knowledge far beyond the current state on the cross talk between nerve fibers and immune cells in the cornea and the impact of such cross talk on corneal nerve health and function. Furthermore, this application suggests in vivo approaches for assessing significance of corneal pDCs, in nerve protection and regeneration. Therefore, this proposal will elucidate the neuro-protective and neuro-regenerative properties of pDCs, may result in novel therapeutic approaches, and is potentially applicable in tissues other than cornea and conditions in which neuro-regeneration is vital, including traumatic nervous system injuries, neurodegenerative diseases, and peripheral neuropathies.