A miR-383-5p signalling hub coordinates the axon regeneration response to inflammation

Neuroinflammation can positively influence axon regeneration following injury in the central nervous system (CNS). Inflammation promotes the release of neurotrophic molecules and stimulates intrinsic pro-regenerative 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 de-represses the mitochondrial antioxidant protein peroxiredoxin-3 (PRDX3) which was required for the pro-regenerative 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 signalling module that promotes inflammation-induced axon regeneration. Significance statement Inflammation can both positively and negatively influence the neuronal response to injury. Identifying molecular signalling pathways that mimic pro-regenerative effects of inflammation while bypassing cytotoxic effects is important for our understanding of the precise functions of inflammation in CNS injury and repair. We demonstrate that miR-383-5p is suppressed in neurons in response to inflammatory stimuli and regulates members of the ciliary neurotrophic factor (CNTF) receptor complex, as well as the expression of an antioxidant protein to improve axon regeneration in an optic nerve crush model. These findings identify a new molecular signalling module that promotes axon regeneration and that may bypass detrimental effects of inflammation.