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Nilisha Fernando, Josephine Wong, Riemke Aggio-Bruce, Yvette Wooff, Riccardo Carlo Natoli; MicroRNA-223 regulates neuroinflammation in retinal degenerations. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4001.
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Excessive inflammation is implicated in neurodegenerative diseases including Age-Related Macular Degeneration (AMD). Regulation of pro-inflammatory cytokine release (including IL-1β) by microglia and macrophages is critical in preventing photoreceptor loss. MicroRNAs (miRNAs) have the ability to target the expression of multiple genes, often within associated pathways. However, there is still a poor understanding of the role of miRNAs in controlling inflammation in the retina. MicroRNA-223 (miR-223) dysregulation has been linked to the progression of neuroinflammatory diseases, although its retinal expression has not been previously studied. Here, we investigated the role of miR-223 in inflammation and cell death using a model of retinal degenerations.
C57BL/6J mice were exposed to photo-oxidative damage (PD), and eyes and retinas were collected for cell death (TUNEL), immunohistochemistry (IBA1) and qPCR for miR-223 and inflammatory gene expression (Il-1β, Nlrp3, Ccl3, Il-6). Mice with no exposure to PD were used as dim-reared controls. In vitro, miR-223 expression in immortalised and primary cell cultures (microglia, Müller cells, RPE, photoreceptors) was determined via qPCR, following inflammatory stimulation. A miR-223 inhibitor was intravitreally injected into PD mice to determine the effect on photoreceptor loss.
Retinal miR-223 expression increased significantly during PD, compared to dim-reared controls (P<0.05). This was associated with an increase in Il-1β expression in PD (P<0.05), as well as dysregulation of Nlrp3, Ccl3 and Il-6 genes in PD (predicted targets of miR-223, P<0.05). In vitro, in stimulated C8B4 immortalised and primary retinal microglia, miR-223 expression was significantly decreased alongside an increase in Il-1β (P<0.05). Conversely, miR-223 was upregulated significantly in 661W photoreceptor-like cells following PD (P<0.05). Injection of a miR-223 inhibitor increased photoreceptor loss in PD (P<0.05).
It is hypothesised that in the retina, photoreceptors express miR-223 and potentially regulate inflammation at the cellular source in microglia and macrophages. Further investigation into the vast array of inflammatory pathways targeted by miR-223 could shed light on novel mechanisms of miR-223 activity in retinal degenerations, including neuroprotection. Regulating miR-223 using mimics may be of therapeutic benefit for neurodegenerative diseases including AMD.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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