Inhibition of microRNA-155 Protects Retinal Function Through Attenuation of Inflammation in Retinal Degeneration

Although extensively investigated in inflammatory conditions, the role of pro-inflammatory microRNAs (miRNAs), miR-155 and miR-146a, has not been well-studied in retinal degenerative diseases. We therefore aimed to explore the role and regulation of these miRNA in the degenerating retina, with a focus on miR-155. C57BL/6J mice were subjected to photo-oxidative damage for up to 5 days to induce focal retinal degeneration. MiR-155 expression was quantified by qRT-PCR in whole retina, serum, and small-medium extracellular vesicles (s-mEVs), and a PrimeFlow™ assay was used to identify localisation of miR-155 in retinal cells. Constitutive miR-155 knockout (KO) mice and miR-155 and miR-146a inhibitors were utilised to determine the role of these miRNA in the degenerating retina. Electroretinography was employed as a measure of retinal function, while histological quantification of TUNEL+ and IBA1+ positive cells was used to quantify photoreceptor cell death and infiltrating immune cells, respectively. Upregulation of miR-155 was detected in retinal tissue, serum and s-mEVs in response to photo-oxidative damage, localising to the nucleus of a subset of retinal ganglion cells and glial cells and in the cytoplasm of photoreceptors. Inhibition of miR-155 showed increased function from negative controls and a less pathological pattern of IBA1+ cell localisation and morphology at 5 days photo-oxidative damage. While neither dim-reared nor damaged miR-155 KO animals showed retinal histological difference from controls, following photo-oxidative damage, miR-155 KO mice showed increased a-wave relative to controls. We therefore consider miR-155 to be associated with the inflammatory response of the retina in response to photoreceptor-specific degeneration.This work would not have been possible without the support of the National Health and Medical Research Council of Australia (NHMRC: 1127705), Retina Australia, The Gordon and Gretel Bootes Foundation and The ANU Translational Fellowshi