Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA.
Department of Pathology, Genentech, Inc., South San Francisco, CA 94080, USA.
Cell Rep. 2021 Mar 9;34(10):108835. doi: 10.1016/j.celrep.2021.108835.
In multiple sclerosis (MS) and other neurological diseases, the failure to repair demyelinated lesions contributes to axonal damage and clinical disability. Here, we provide evidence that Mertk, a gene highly expressed by microglia that alters MS risk, is required for efficient remyelination. Compared to wild-type (WT) mice, Mertk-knockout (KO) mice show impaired clearance of myelin debris and remyelination following demyelination. Using single-cell RNA sequencing, we characterize Mertk-influenced responses to cuprizone-mediated demyelination and remyelination across different cell types. Mertk-KO brains show an attenuated microglial response to demyelination but an elevated proportion of interferon (IFN)-responsive microglia. In addition, we identify a transcriptionally distinct subtype of surviving oligodendrocytes specific to demyelinated lesions. The inhibitory effect of myelin debris on remyelination is mediated in part by IFNγ, which further impedes microglial clearance of myelin debris and inhibits oligodendrocyte differentiation. Together, our work establishes a role for Mertk in microglia activation, phagocytosis, and migration during remyelination.
在多发性硬化症 (MS) 和其他神经疾病中，髓鞘脱失病变的修复失败导致轴突损伤和临床残疾。在这里，我们提供的证据表明，Mertk 是一种高度表达于小胶质细胞的基因，它改变了 MS 的风险，对于有效的髓鞘再生是必需的。与野生型 (WT) 小鼠相比，Mertk 敲除 (KO) 小鼠在脱髓鞘后表现出髓鞘碎片清除和髓鞘再生受损。通过单细胞 RNA 测序，我们对 Mertk 影响的对杯状朊病毒介导的脱髓鞘和髓鞘再生的反应进行了跨不同细胞类型的特征描述。Mertk-KO 大脑显示出对脱髓鞘反应的减弱，但干扰素 (IFN) 反应性小胶质细胞的比例升高。此外，我们还鉴定出一种在脱髓鞘病变中特有的、转录上不同的存活少突胶质细胞亚型。髓鞘碎片对髓鞘再生的抑制作用部分是由 IFNγ 介导的，它进一步阻碍了小胶质细胞对髓鞘碎片的清除，并抑制了少突胶质细胞的分化。总之，我们的工作确立了 Mertk 在髓鞘再生中小胶质细胞激活、吞噬和迁移中的作用。
