Neuroinflammation can positively influence axon regeneration following injury in the central nervous system. Inflammation promotes the release of neurotrophic molecules and stimulates intrinsic proregenerative molecular machinery in neurons, but the detailed mechanisms driving this effect are not fully understood. We evaluated how microRNAs are regulated in retinal neurons in response to intraocular inflammation to identify their potential role in axon regeneration. We found that miR-383-5p is downregulated in retinal ganglion cells in response to zymosan-induced intraocular inflammation. MiR-383-5p downregulation in neurons is sufficient to promote axon growth in vitro, and the intravitreal injection of a miR-383-5p inhibitor into the eye promotes axon regeneration following optic nerve crush. MiR-383-5p directly targets ciliary neurotrophic factor (CNTF) receptor components, and miR-383-5p inhibition sensitizes adult retinal neurons to the outgrowth-promoting effects of CNTF. Interestingly, we also demonstrate that CNTF treatment is sufficient to reduce miR-383-5p levels in neurons, constituting a positive-feedback module, whereby initial CNTF treatment reduces miR-383-5p levels, which then disinhibits CNTF receptor components to sensitize neurons to the ligand. Additionally, miR-383-5p inhibition derepresses the mitochondrial antioxidant protein peroxiredoxin-3 (PRDX3) which was required for the proregenerative effects associated with miR-383-5p loss-of-function in vitro. We have thus identified a positive-feedback mechanism that facilitates neuronal CNTF sensitivity in neurons and a new molecular signaling module that promotes inflammation-induced axon regeneration.

神经炎症可以对中枢神经系统损伤后的轴突再生产生积极影响。炎症促进神经营养分子的释放并刺激神经元中内在的促再生分子机制，但驱动这种效应的详细机制尚不完全清楚。我们评估了 microRNA 如何在视网膜神经元中响应眼内炎症进行调节，以确定它们在轴突再生中的潜在作用。我们发现 miR-383-5p 在视网膜神经节细胞中响应酵母聚糖诱导的眼内炎症而下调。神经元中的 miR-383-5p 下调足以在体外促进轴突生长，玻璃体内注射 miR-383-5p 抑制剂到眼中可促进视神经挤压后的轴突再生。miR-383-5p 直接靶向睫状神经营养因子 （CNTF） 受体成分，miR-383-5p 抑制使成年视网膜神经元对 CNTF 的生长促进作用敏感。有趣的是，我们还证明 CNTF 处理足以降低神经元中的 miR-383-5p 水平，构成一个正反馈模块，因此初始 CNTF 处理降低 miR-383-5p 水平，然后解除抑制 CNTF 受体成分使神经元对配体敏感。此外，miR-383-5p 抑制会抑制线粒体抗氧化蛋白过氧化物还蛋白-3 （PRDX3），这是体外与 miR-383-5p 功能丧失相关的促再生作用所必需的。因此，我们确定了一种促进神经元中神经元 CNTF 敏感性的正反馈机制和一种促进炎症诱导的轴突再生的新分子信号传导模块。