Inhibition of microRNA-155 Protects Retinal Function Through Attenuation of Inflammation in Retinal Degeneration
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Inhibition of microRNA-155 Protects Retinal Function Through Attenuation of Inflammation in Retinal Degeneration Riemke Aggio-Bruce 1,2 & Joshua A. Chu-Tan 1,2 & Yvette Wooff 1,2 & Adrian V. Cioanca 1 & Ulrike Schumann 1 & Riccardo Natoli 1,2 Received: 4 August 2020 / Accepted: 1 October 2020 # The Author(s) 2020
Abstract 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. Keywords Retina . miRNA . miR-155 . Microglia . Macrophage . Inflammation . Photo-oxidative damage
Abbreviations AGO Argonaute ALS Amyotrophic lateral sclerosis AMD Age-related macular degeneration ANOVA Analysis of variance
ANTXR2 ANU ARVO BDNF
Anthrax toxin receptor 2 Australian National University Association for Research in Vision and Ophthalmology Brain-derived neurotrophic factor
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02158-z) contains supplementary material, which is available to authorized users. * Riccardo Natoli [email protected]
Adrian V. Cioanca [email protected]
Riemke Aggio-Bruce [email protected]
Ulrike Schumann [email protected]
Joshua A. Chu-Tan [email protected]
1
The John Curtin School of Medical Research, The Australian National University, Garran Road, Acton, Australian Capital Territory 2601, Australia
Yvette Wooff
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