Frontiers in Cell and Developmental Biology (Jun 2020)

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,
  • Riemke Aggio-Bruce,
  • Adrian V. Cioanca,
  • Yvette Wooff,
  • Yvette Wooff,
  • Joshua A. Chu-Tan,
  • Joshua A. Chu-Tan,
  • Ulrike Schumann,
  • Chinh Ngo,
  • Rohan W. Essex,
  • Camilla Dorian,
  • Sarah A. Robertson,
  • Si Ming Man,
  • Jan Provis,
  • Riccardo Natoli,
  • Riccardo Natoli

DOI
https://doi.org/10.3389/fcell.2020.00516
Journal volume & issue
Vol. 8

Abstract

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IntroductionMicroRNAs (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.MethodsmiR-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).ResultsRetinal 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.ConclusionmiR-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.

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