MicroRNA-223 Regulates Retinal Function and Inflammation in the Healthy and Degenerating Retina

Nilisha Fernando, Josephine H.C. Wong, Shannon Das, Catherine Dietrich, Riemke Aggio-Bruce, Adrian V. Cioanca, Yvette Wooff, Joshua A. Chu-Tan, Ulrike Schumann, Chinh Ngo, Rohan W. Essex, Camilla Dorian, Sarah A. Robertson, Si Ming Man, Jan Provis, Riccardo Natoli*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    16 Citations (Scopus)


    Introduction: MicroRNAs (miRNAs) are small, non-coding RNA molecules that have powerful regulatory properties, with the ability to regulate multiple messenger RNAs (mRNAs) and biological pathways. MicroRNA-223-3p (miR-223) is known to be a critical regulator of the innate immune response, and its dysregulation is thought to play a role in inflammatory disease progression. Despite miR-223 upregulation in numerous neurodegenerative conditions, largely in cells of the myeloid lineage, the role of miR-223 in the retina is relatively unexplored. Here, we investigated miR-223 in the healthy retina and in response to retinal degeneration. Methods: miR-223-null mice were investigated in control and photo-oxidative damage-induced degeneration conditions. Encapsulated miR-223 mimics were intravitreally and intravenously injected into C57BL/6J wild-type mice. Retinal functional responses were measured using electroretinography (ERG), while extracted retinas were investigated by retinal histology (TUNEL and immunohistochemistry) and molecular analysis (qPCR and FACS). Results: Retinal function in miR-223–/– mice was adversely affected, indicating that miR-223 may be critical in regulating the retinal response. In degeneration, miR-223 was elevated in the retina, circulating serum, and retinal extracellular vesicles. Conversely, retinal microglia and macrophages displayed a downregulation of miR-223. Further, isolated CD11b+ inflammatory cells from the retinas and circulation of miR-223-null mice showed an upregulation of pro-inflammatory genes that are critically linked to retinal inflammation and progressive photoreceptor loss. Finally, both local and systemic delivery of miR-223 mimics improved retinal function in mice undergoing retinal degeneration. Conclusion: miR-223 is required for maintaining normal retinal function, as well as regulating inflammation in microglia and macrophages. Further investigations are required to determine the targets of miR-223 and their key biological pathways and interactions that are relevant to retinal diseases. Future studies should investigate whether sustained delivery of miR-223 into the retina is sufficient to target these pathways and protect the retina from progressive degeneration.

    Original languageEnglish
    Article number516
    JournalFrontiers in Cell and Developmental Biology
    Publication statusPublished - 26 Jun 2020


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