Thompson Cassandra E, Loshi Sheila, Carew Samantha J, Berry Tangyne R, Parsons Matthew P, Antel Jack P, Moore Craig S
Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Eur J Neurosci. 2025 Sep;62(5):e70248. doi: 10.1111/ejn.70248.
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.
多发性硬化症（MS）是一种慢性免疫介导的中枢神经系统（CNS）脱髓鞘疾病，临床上最常表现为复发形式。在MS病变中，少突胶质前体细胞（OPC）分化为成熟的髓鞘形成少突胶质细胞并介导修复。进一步了解负责OPC分化的分子机制无疑将影响MS未来治疗的方向。在MS病变中，先前已证明几种不同的微小RNA会影响炎症和修复机制，包括OPC分化和存活。具体而言，miR-146b-5p是一种抗炎微小RNA，在活动性MS病变的白质星形胶质细胞中上调。我们的结果表明，在纯原代人星形胶质细胞和小鼠星形胶质细胞中增加miR-146b-5p水平，在IL-1β刺激后可显著降低IL-6和CXCL10的产生，而在含有小胶质细胞的混合胶质细胞培养物中未观察到这种效果。此外，当星形胶质细胞中miR-146b-5p水平增加时，IL-1β对OPC分化和复杂性的抑制作用被逆转；在有小胶质细胞存在的情况下未观察到差异。在星形胶质细胞中，miR-146b-5p水平的增加导致traf6和irak1表达显著降低，这是已知的增强星形胶质细胞促炎活性的两个关键信号分子。总之，这些结果表明miR-146b-5p是一种与MS相关的微小RNA，它以促进OPC生长和形态复杂性的方式调节星形胶质细胞功能。此外，我们的结果进一步证明需要考虑MS病变中发生的复杂胶质细胞-胶质细胞相互作用及其对与CNS损伤和修复相关的细胞和分子机制的总体影响。
