Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305-5125;
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, South Korea.
Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E8072-E8080. doi: 10.1073/pnas.1710566114. Epub 2017 Sep 5.
Ineffective myelin debris clearance is a major factor contributing to the poor regenerative ability of the central nervous system. In stark contrast, rapid clearance of myelin debris from the injured peripheral nervous system (PNS) is one of the keys to this system's remarkable regenerative capacity, but the molecular mechanisms driving PNS myelin clearance are incompletely understood. We set out to discover new pathways of PNS myelin clearance to identify novel strategies for activating myelin clearance in the injured central nervous system, where myelin debris is not cleared efficiently. Here we show that Schwann cells, the myelinating glia of the PNS, collaborate with hematogenous macrophages to clear myelin debris using TAM (Tyro3, Axl, Mer) receptor-mediated phagocytosis as well as autophagy. In a mouse model of PNS nerve crush injury, Schwann cells up-regulate TAM phagocytic receptors Axl and Mertk following PNS injury, and Schwann cells lacking both of these phagocytic receptors exhibit significantly impaired myelin phagocytosis both in vitro and in vivo. Autophagy-deficient Schwann cells also display reductions in myelin clearance after mouse nerve crush injury, as has been recently shown following nerve transection. These findings add a mechanism, Axl/Mertk-mediated myelin clearance, to the repertoire of cellular machinery used to clear myelin in the injured PNS. Given recent evidence that astrocytes express Axl and Mertk and have previously unrecognized phagocytic potential, this pathway may be a promising avenue for activating myelin clearance after CNS injury.
无效的髓鞘碎片清除是导致中枢神经系统再生能力差的一个主要因素。相比之下，外周神经系统（PNS）损伤后髓鞘碎片的快速清除是该系统具有显著再生能力的关键之一，但驱动 PNS 髓鞘清除的分子机制尚不完全清楚。我们着手发现 PNS 髓鞘清除的新途径，以确定在中枢神经系统（其中髓鞘碎片不能有效清除）中激活髓鞘清除的新策略。在这里，我们表明，施万细胞（PNS 的髓鞘形成胶质细胞）与血液来源的巨噬细胞合作，通过 TAM（Tyro3、Axl、Mer）受体介导的吞噬作用以及自噬来清除髓鞘碎片。在 PNS 神经挤压损伤的小鼠模型中，PNS 损伤后施万细胞上调 TAM 吞噬受体 Axl 和 Mertk，并且缺乏这两种吞噬受体的施万细胞在体外和体内均表现出明显受损的髓鞘吞噬作用。自噬缺陷的施万细胞在小鼠神经挤压损伤后也显示出髓鞘清除减少，正如最近在神经横断后所显示的那样。这些发现为 PNS 损伤中用于清除髓鞘的细胞机制增加了一种机制，即 Axl/Mertk 介导的髓鞘清除。鉴于最近的证据表明星形胶质细胞表达 Axl 和 Mertk 并具有以前未被认识到的吞噬能力，这条途径可能是在中枢神经系统损伤后激活髓鞘清除的一个很有前途的途径。
