MiR‐146b‐5p Decreases Cytokine Release From Astrocytes and Preserves Oligodendrocyte Progenitor Cell Complexity During Inflammation

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system (CNS) and is most often clinically presented in a relapsing form. Within MS lesions, oligodendrocyte progenitor cells (OPCs) differentiate into mature myelinating oligodendrocytes and mediate repair. A further understanding of the molecular mechanisms responsible for OPC differentiation will undoubtedly influence the direction of future treatments in MS. In MS lesions, several distinct microRNAs have been previously demonstrated to influence both inflammatory and repair mechanisms, including OPC differentiation and survival. Specifically, miR-146b-5p is an anti-inflammatory microRNA that is upregulated in white matter astrocytes within active MS lesions. Our results demonstrate that increasing miR-146b-5p levels within pure primary human and murine astrocytes significantly decreases IL-6 and CXCL10 production upon IL-1β stimulation, an effect not observed in mixed glial cultures containing microglia. In addition, the inhibitory effects of IL-1β on OPC differentiation and complexity were reversed when miR-146b-5p levels were increased in astrocytes; no differences were observed in the presence of microglia. In astrocytes, the increase in miR-146b-5p levels led to a significant reduction in traf6 and irak1 expression, which are two critical signaling molecules known to enhance the pro-inflammatory activity of astrocytes. Together, these results suggest that miR-146b-5p is an MS-relevant microRNA that regulates astrocyte function in a manner that fosters OPC growth and morphological complexity. Furthermore, our results further demonstrate the need to consider the complex glial-glial interactions occurring within MS lesions and its overall influence on cellular and molecular mechanisms related to CNS injury and repair.