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

Abstract

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 damageinduced 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

Disruption ofmiR-18aalters proliferation, photoreceptor replacement kinetics, inflammatory signaling and microglia/macrophage numbers during retinal regeneration in zebrafish

“…While miR-18a is the first known miRNA to play important roles in both neuronal regeneration and inflammation in the injured retina, several other miRNAs are known to be key regulators of inflammation [74] and could be important for future retinal studies. For example, in patients with diabetic retinopathy, decreased miR-146b-3p was associated with increased vascular inflammation [75] and in the healthy and degenerating mouse retina, miR-223 is an important inflammatory suppressor [76]. MicroRNAs can also have pro-inflammatory functions; an example is miR-155 , which was shown to promote inflammation in the degenerating mouse retina, Conversely, inhibiting miR-155 in this context was neuroprotective [77].…”

“…For example, in patients with diabetic retinopathy, decreased miR-146b-3p was associated with increased vascular inflammation [75] and in the healthy and degenerating mouse retina, miR-223 is an important inflammatory suppressor [76].…”

Extracellular Vesicles as Biomarkers and Therapeutics for Inflammatory Eye Diseases

“…Electroretinograms of mouse eyes treated with GW4869 showed reduced retinal function and increased levels of inflammation and cell death. In another study by the same group, miR-223–3p, an important regulator of the innate immune response, was found to be elevated in EVs from degenerating retina with retinal function being adversely affected . Other miRNA such as miR-155 have also been found to be elevated in EVs from degenerating retina, with pro-inflammatory markers such as Iba1 being reduced in response to its inhibition .…”

“…In another study by the same group, miR-223−3p, an important regulator of the innate immune response, was found to be elevated in EVs from degenerating retina with retinal function being adversely affected. 117 Other miRNA such as miR-155 have also been found to be elevated in EVs from degenerating retina, with pro-inflammatory markers such as Iba1 being reduced in response to its inhibition. 118 These results demonstrate the important roles retinal EVs and their cargo play in maintaining retinal homeostasis and regulating the immune response.…”

Neuroinflammation in retinitis pigmentosa: Therapies targeting the innate immune system

“…By downregulating microglial activation and PR mortality, miR-204 alters the expression profiles of transgenic retinas toward those of healthy retinas ( 114 ). In addition, miR-223 is required for the regulation of microglial inflammation and the maintenance of normal retinal function ( 247 ).…”