MicroRNA-223 protects neurons from degeneration in Experimental Autoimmune Encephalomyelitis

Abstract

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and neurodegeneration in the brain, spinal cord and optic nerve. Neuronal degeneration and death underlie progressive forms of MS and cognitive dysfunction. Neuronal damage is triggered by numerous harmful factors in the brain that engage diverse signalling cascades in neurons thus therapeutic approaches to protect neurons will need to focus on agents that can target broad biological processes. To target the broad spectrum of signaling events that mediate neurodegeneration in MS we have focused on non-coding small microRNAs (miRNAs). microRNAs are epigenetic regulators of protein expression, targeting messenger RNAs (mRNAs) and inhibiting their translation. Dysregulation of miRNAs has been described in many neurodegenerative diseases including MS. In this study we identified two miRNAs, miR-223-3p and miR-27a-3p, that were upregulated in neurons in the experimental autoimmune encephalomyelitis (EAE) mouse model of CNS inflammation and in active MS lesions. Overexpression of miR-27a-3p or miR-223-3p protected dissociated cortical neurons from degeneration in response to peripheral blood mononuclear cell conditioned media (PBMC-CM). Introduction of miR-223-3p in vivo in mouse retinal ganglion cells (RGCs) protected RGC axons from degeneration in the EAE model. By in silico analysis we found that mRNAs in the glutamate receptor (GluR) pathway are enriched in miR-27a-3p and miR-223-3p targets. Antagonism of the GluR pathway protected neurons from PBMC-CM-dependent degeneration. Our results suggest that miR-223-3p and miR-27a-3p are upregulated in response to inflammation to mediate a compensatory neuroprotective gene expression program that desensitizes neurons to glutamate by downregulating mRNAs involved in GluR signalling.

MiR-30e-5p inhibits the migration and invasion of nasopharyngeal carcinoma via regulating the expression of MTA1

“…Dysregulated induce the dysregulation of normal regulatory networks by functioning as tumor suppressors or oncogenes [12]. Mature miRNAs modulate the processes of gene expressions through targeting the 3 untranslated regions (3 UTR) of downstream mRNAs and restraining protein translation or initiating mRNA degradation of many mRNA transcripts [13]. These molecules typically reduce the stability of mRNAs, including certain genes mediating tumorigenesis such as apoptosis and invasion [14].…”

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

“…Without miR-223, retinal function appears to be worsened, whereas both locally and systemically delivered miR-223 mimics led to an improvement in retinal function. This again demonstrates that miR-223 may be required in the preservation of the retinal response, perhaps by promoting microglial homeostatic maintenance ( Galloway et al, 2019 ; Guo et al, 2019 ), or through neuroprotection and GluR signaling as discussed earlier ( Harraz et al, 2012 ; Morquette et al, 2019 ). When delivered locally, miR-223 supplementation also protected mice from photoreceptor loss.…”

“…The ERG b-wave was also dampened in miR-223-null photo-oxidative damaged mice, indicating reduced ON-bipolar and Müller cell activity. A potential loss of miR-223-mediated neuroprotection could again have contributed to both of these observations ( Harraz et al, 2012 ; Morquette et al, 2019 ). These data point to miR-223 having dual protective and damaging roles in the degenerating retina.…”

“…It is possible that reduced C1qa in miR-223-null retinas contributes to altered retinal function in normal conditions; although as C1qa is not a known target of miR-223, this could be occurring through other microglial components that may activate the complement system. Other studies have suggested a role for miR-223 in the neuroprotection of photoreceptors and second-order neurons, showing that the expression of glutamate receptor (GluR) subunits may be regulated by miR-223 ( Harraz et al, 2012 ; Morquette et al, 2019 ). In particular, GluR2 and NR2B have been identified as potential targets of miR-223 ( Harraz et al, 2012 ), with GluR2 thought to be expressed by bipolar cells housed within the INL ( Lin et al, 2012 ).…”

The Role of MicroRNAs in Repair Processes in Multiple Sclerosis

“…This upregulation is recapitulated in demyelinated mouse hippocampal neurons and is associated with memory dysfunction, while remyelination reversed these changes [ 75 ]. MiR-223—which also has a role in microglia and macrophages in remyelination—and miR-27a are upregulated in retinal ganglion cells in EAE following local damage, and are associated with neuroprotection from glutamate toxicity [ 61 ]. In the spinal ventral horn during EAE, Vitamin D Receptor (VDR) expression on neurons is reduced, while miR-125a is upregulated, and both activation of the VDR and inhibition of miR-125a are associated with reduced clinical scores, suggesting a neuroprotective role [ 59 ].…”