RT Journal Article
SR Electronic
T1 A miR-383-5p Signaling Hub Coordinates the Axon Regeneration Response to Inflammation
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP e1822232024
DO 10.1523/JNEUROSCI.1822-23.2024
VO 44
IS 44
A1 Hintermayer, Matthew A.
A1 Juźwik, Camille A.
A1 Morquette, Barbara
A1 Hua, Elizabeth
A1 Zhang, Julia
A1 Drake, Sienna
A1 Shi, Shan Shan
A1 Rambaldi, Isabel
A1 Vangoor, Vamshi
A1 Pasterkamp, Jeroen
A1 Moore, Craig
A1 Fournier, Alyson E.
YR 2024
UL http://www.jneurosci.org/content/44/44/e1822232024.abstract
AB 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.