Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of the Ministry of Education and the Collaborative Innovation Center for Brain Science, Second Military Medical University, Shanghai, China.
Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
EMBO Rep. 2017 Oct;18(10):1801-1816. doi: 10.15252/embr.201643668. Epub 2017 Aug 14.
The regulation of inflammation is pivotal for preventing the development or reoccurrence of multiple sclerosis (MS). A biased ratio of high-M1 versus low-M2 polarized microglia is a major pathological feature of MS Here, using microarray screening, we identify the long noncoding RNA (lncRNA) GAS5 as an epigenetic regulator of microglial polarization. Gain- and loss-of-function studies reveal that GAS5 suppresses microglial M2 polarization. Interference with GAS5 in transplanted microglia attenuates the progression of experimental autoimmune encephalomyelitis (EAE) and promotes remyelination in a lysolecithin-induced demyelination model. In agreement, higher levels of GAS5 are found in amoeboid-shaped microglia in MS patients. Further, functional studies demonstrate that GAS5 suppresses transcription of TRF4, a key factor controlling M2 macrophage polarization, by recruiting the polycomb repressive complex 2 (PRC2), thereby inhibiting M2 polarization. Thus, GAS5 may be a promising target for the treatment of demyelinating diseases.
炎症的调节对于预防多发性硬化症（MS）的发展或复发至关重要。高 M1 与低 M2 极化小胶质细胞的偏置比例是 MS 的主要病理特征。在这里，我们使用微阵列筛选鉴定了长非编码 RNA（lncRNA）GAS5 作为小胶质细胞极化的表观遗传调节剂。增益和功能丧失研究表明，GAS5 抑制小胶质细胞 M2 极化。干扰移植的小胶质细胞中的 GAS5 可减轻实验性自身免疫性脑脊髓炎（EAE）的进展，并在溶血磷脂诱导的脱髓鞘模型中促进髓鞘再生。一致地，在 MS 患者中发现了具有阿米巴样形态的小胶质细胞中 GAS5 水平升高。此外，功能研究表明，GAS5 通过募集多梳抑制复合物 2（PRC2）来抑制 M2 极化，从而抑制转录因子 4（TRF4）的转录，TRF4 是控制 M2 巨噬细胞极化的关键因素。因此，GAS5 可能是治疗脱髓鞘疾病的有前途的靶标。
