Neutrophil driven recovery from traumatic and ischemic optic neuropathy

摘要 轴索病变是视神经炎、缺血性视神经病变、 青光眼和外伤性视神经损伤。在所有这些情况下，永久性视力丧失是次要的，在 在很大程度上，是由于视神经的输出神经元--视网膜神经节细胞(RGC)无法存活和 再生他们的轴突。迫切需要开发克服障碍的新的治疗干预措施。 修复成年中枢神经系统，促进RGC存活和轴突再生。这里提出的研究是 基于我们发现的一种新的促再生中性粒细胞亚群，其特征是细胞表面 表型Ly6GlowCD14+，聚集在眼后房或腹膜腔 在局部使用酵母细胞壁抽提物后，酵母多糖。这些中性粒细胞呈环状。 并高水平表达精氨酸酶-1和CD206的转录本。在初步研究中，我们 酵母多糖诱导Ly6GlowCD14+中性粒细胞刺激RGC突起生长 在体外共培养中。此外，过继转移纯化的酵母多糖可诱导Ly6GlowCD14+中性粒细胞 直接进入视神经挤压(ONC)损伤小鼠的玻璃体足以将RGC从细胞死亡中拯救出来 刺激切断的RGC轴突再生。目前提案的总体目标是增加 我们对修复体在眼内蓄积和功能的理解 Ly6GlowCD14+中性粒细胞，并评估它们在另一种视神经损伤模型中的疗效。在AIM 1，我们将询问促进眼内Ly6GlowCD14+中性粒细胞聚集的因素。 模特。我们假设所涉及的趋化因子不同于那些策划贩卖 成熟的、传统的中性粒细胞。在目标2中，我们将确定Arg1+单核细胞的作用，即 在RGC保护和轴突中，Ly6GlowCD14+中性粒细胞最初进入眼睛后被招募到眼睛 再生。在目标3中，我们将验证我们的假设：Ly6Glow CD14+中性粒细胞介导的眼部修复 转化为RGC损伤的另一种模型，继发于缺血。我们希望，由 我们的研究将最终导致基于细胞的创新疗法和/或免疫调节的发展 具有神经保护/再生功能的药物，可恢复视神经患者丧失的神经功能 视神经损伤以视神经病变为特征的创伤或其他情况

Abstract Axonopathy is an early and prominent pathological feature of optic neuritis, ischemic optic neuropathy, glaucoma, and traumatic optic nerve injury. Permanent loss of vision in all of these conditions is secondary, in large part, to a failure of retinal ganglion cells (RGC), the output neurons of the optic nerve, to survive and regenerate their axons. There is a dire need to develop novel therapeutic interventions that overcome barriers to repair in the adult CNS and promote RGC survival and axonal regrowth. The studies proposed here are based on our discovery of a novel subset of pro-regenerative neutrophils, characterized by the cell surface phenotype Ly6GlowCD14+, that accumulate in the posterior chamber of the eye or the peritoneal cavity following local administration of the yeast cell wall extract, zymosan. These neutrophils bear a ring-form nucleus and express high levels of transcripts for arginase-1 and CD206. In preliminary studies we demonstrated that zymosan elicited Ly6GlowCD14+ neutrophils stimulate neurite outgrowth of dissociated RGC in co-cultures in vitro. Furthermore, adoptive transfer of purified zymosan elicited Ly6GlowCD14+ neutrophils directly into the vitreous of mice with optic nerve crush (ONC) injury is sufficient to rescue RGC from cell death and to stimulate the regrowth of severed RGC axons. The overall goals of the current proposal are to increase our understanding of the pathways that underlie the intraocular accumulation and function of reparative Ly6GlowCD14+ neutrophils, and to assess their efficacy in an alternative model of optic nerve damage. In Aim 1, we will interrogate the factors that promote the intraocular accumulation of Ly6GlowCD14+ neutrophils in our model. We hypothesize that the chemokines involved differ from those that orchestrate the trafficking of mature, conventional neutrophils. In Aim 2, we will determine the role of the arg1+ monocytes, that are recruited to the eye following the initial entry of Ly6GlowCD14+ neutrophils, in RGC protection and axon regeneration. In Aim 3, we will test our hypothesis that Ly6Glow CD14+ neutrophil mediated ocular repair translates to another model of RGC injury, secondary to ischemia. We are hopeful that the data generated by our study will ultimately lead to the development of innovative cell based therapies and/ or immunomodulatory drugs with neuroprotective/ regenerative properties that restore lost neurological functions in patients with optic trauma or other conditions characterized by optic neuropathy.