Gene Editing and Screening Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Translational Medicine, Celgene Corporation, Summit, NJ, USA.
Sci Rep. 2018 Jun 20;8(1):9392. doi: 10.1038/s41598-018-27559-y.
In multiple sclerosis (MS), demyelinated CNS lesions fail to sufficiently remyelinate, despite the presence of oligodendrocyte precursor cells (OPCs) capable of differentiating into mature oligodendrocytes. MS lesions contain damaged myelin debris that can inhibit OPC maturation and hinder repair. rHIgM22 is an experimental human recombinant IgM antibody that promotes remyelination in animal models and is being examined in patients with MS. rHIgM22 binds to CNS myelin and partially rescues OPC process outgrowth on myelin. Since rHIgM22 does not affect OPC process outgrowth in vitro on permissive substrate, we examined the possibility that it acts by enhancing phagocytic clearance of myelin debris by microglia. In this study, we tested if rHIgM22 binding could tag myelin for microglial phagocytosis. A mouse microglial cell line and primary rat microglia were treated with myelin and rHIgM22 and assayed for myelin phagocytosis. We found that: 1) rHIgM22 stimulates myelin phagocytosis in a dose-dependent manner; 2) rHIgM22-mediated myelin phagocytosis requires actin polymerization; and 3) rHIgM22-stimulation of myelin phagocytosis requires activity of rHIgM22 Fc domain and activation of Complement Receptor 3. Since myelin inhibits OPC differentiation, stimulation of phagocytic clearance of damaged myelin may be an important means by which rHIgM22 promotes remyelination.
在多发性硬化症 (MS) 中，尽管存在能够分化为成熟少突胶质细胞的少突胶质前体细胞 (OPC)，脱髓鞘的中枢神经系统病变仍未能充分得到修复。MS 病变中含有可抑制 OPC 成熟并阻碍修复的受损髓磷脂碎片。rHIgM22 是一种实验性人重组 IgM 抗体，可在动物模型中促进髓鞘再生，目前正在 MS 患者中进行研究。rHIgM22 与中枢神经系统髓磷脂结合，并部分挽救髓磷脂上 OPC 突起的生长。由于 rHIgM22 不会影响体外在允许底物上 OPC 突起的生长，因此我们研究了它通过增强小胶质细胞对髓磷脂碎片的吞噬清除作用来发挥作用的可能性。在这项研究中，我们测试了 rHIgM22 结合是否可以标记小胶质细胞吞噬髓磷脂。用髓磷脂和 rHIgM22 处理小鼠小胶质细胞系和原代大鼠小胶质细胞，并检测髓磷脂吞噬作用。我们发现：1）rHIgM22 以剂量依赖性方式刺激髓磷脂吞噬作用；2）rHIgM22 介导的髓磷脂吞噬作用需要肌动蛋白聚合；3）rHIgM22 刺激髓磷脂吞噬作用需要 rHIgM22 Fc 结构域的活性和补体受体 3 的激活。由于髓磷脂抑制 OPC 分化，因此刺激受损髓磷脂的吞噬清除可能是 rHIgM22 促进髓鞘再生的重要手段。
