MicroRNA-124 is redistributed from neurons to glia to reduce inflammation and slow progressive retinal degeneration

Abstract

Purpose : MicroRNA-124 (miR-124) is highly expressed in neurons and is largely considered to be involved in neuronal development. MiR-124 has also been shown to act as a powerful anti-inflammatory molecule, regulating the expression of pro-inflammatory chemokine, CCL2. However, the role of miR-124 in the degenerating retina is not well established. We sought to determine the cellular location and function of miR-124 in the degenerating retina and demonstrate its potential for reducing retinal inflammation and slowing focal degeneration.

Methods : In situ hybridization was used to localize the expression of miR-124 in AMD tissue, as well as rodent retinae after photo-oxidative damage (PD, 100K lux, 5 days). Luciferase assays using the 3’UTR vector for Ccl2 were performed in vitro for miR-124 target validation in retinal cells. MiR-124 mimics were delivered intravitreally, and following 5 day PD, retinae were assessed for photoreceptor cell death (TUNEL), gene expression (qRT-PCR), histology (immunohistochemistry) and function (electroretinography).

Results : In both AMD tissue and PD rodent tissue, expression of miR-124 decreased compared to age-matched healthy and dim-reared specimen respectively. MiR-124 was localized to both neuronal and glial (Müller) cells, and redistributed from Müller cell end feet to the Müller cell bodies (inner nuclear layer) following degeneration. In isolated Müller cells, we showed abundant expression of miR-124 in normal rodent retina with a decrease in expression levels following PD (P<0.05). Intravitreal delivery of miR-124 mimics, compared to a scrambled miRNA treatment, reduced retinal Ccl2 expression and mononuclear phagocyte infiltration, concurrent with improved retinal function (P<0.05). We also confirmed Ccl2 as one of the targets of miR-124 in retinal cells.

Conclusions : We have demonstrated that the anti-inflammatory microRNA, miR-124, is redistributed within the retinal layers, from neuronal to glial, following retinal degeneration. Further, we show that reduced expression of miR-124 is correlated with disease progression, and that increasing availability of miR-124 reduces retinal inflammation. This work validates the use of miR-124 as a potential therapeutic for neurodegenerative diseases where inflammation is a facet, such as Age-Related Macular Degeneration (AMD).

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.