Montréal Neurological Institute, McGill University, Montréal, Quebec H3A 2B4, Canada.
Department of Translation Neuroscience, University Medical Center Brain Center, Utrecht University, Utrecht 3584 CG, Netherlands.
J Neurosci. 2024 Oct 30;44(44):e1822232024. doi: 10.1523/JNEUROSCI.1822-23.2024.
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.
神经炎症可以积极影响中枢神经系统损伤后的轴突再生。炎症促进神经营养分子的释放，并刺激神经元中的固有促再生分子机制，但驱动这种效应的详细机制尚不完全清楚。我们评估了 microRNAs 在视网膜神经元中如何响应眼内炎症而被调节，以确定它们在轴突再生中的潜在作用。我们发现，miR-383-5p 在应对酵母聚糖诱导的眼内炎症时在视网膜神经节细胞中下调。神经元中 miR-383-5p 的下调足以促进体外轴突生长，并且将 miR-383-5p 抑制剂眼内注射到眼睛中可以促进视神经挤压后轴突的再生。miR-383-5p 直接靶向睫状神经营养因子 (CNTF) 受体成分，并且 miR-383-5p 抑制使成年视网膜神经元对 CNTF 的促生长作用敏感。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，构成正反馈模块，其中初始 CNTF 处理降低 miR-383-5p 水平，然后解除 CNTF 受体成分的抑制作用，使神经元对配体敏感。此外，miR-383-5p 抑制解除了线粒体抗氧化蛋白过氧化物还原酶 3 (PRDX3) 的抑制，PRDX3 在与体外 miR-383-5p 功能丧失相关的促再生作用中是必需的。因此，我们鉴定了一种正反馈机制，该机制促进神经元中 CNTF 的敏感性，以及一种新的分子信号模块，该模块促进炎症诱导的轴突再生。
