Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
Department of Orthopaedic Surgery, National Hospital Organization, Hokkaido Medical Center, Sapporo, Japan.
Cell Mol Life Sci. 2022 May 10;79(6):289. doi: 10.1007/s00018-022-04310-5.
Accumulating evidences suggest that M2 macrophages are involved with repair processes in the nervous system. However, whether M2 macrophages can promote axon regeneration by directly stimulating axons nor its precise molecular mechanism remains elusive. Here, the current study demonstrated that typical M2 macrophages, which were generated by IL4 simulation, had the capacity to stimulate axonal growth by their direct effect on axons and that the graft of IL4 stimulated macrophages into the region of Wallerian degeneration enhanced axon regeneration and improved functional recovery after PNI. Importantly, uPA (urokinase plasminogen activator)-uPA receptor (uPAR) was identified as the central axis underlying the axon regeneration effect of IL4 stimulated macrophages. IL4 stimulated macrophages secreted uPA, and its inhibition abolished their axon regeneration effect. Injured but not intact axons expressed uPAR to be sensitive to uPA. These results unveil a cellular and molecular mechanism underlying the macrophage related axon regeneration and provide a basis of a novel therapy for PNI.
越来越多的证据表明，M2 巨噬细胞参与神经系统的修复过程。然而，M2 巨噬细胞是否可以通过直接刺激轴突来促进轴突再生，以及其确切的分子机制仍不清楚。本研究表明，IL4 模拟产生的典型 M2 巨噬细胞具有通过直接作用于轴突刺激轴突生长的能力，将 IL4 刺激的巨噬细胞移植到 Wallerian 变性区域可增强轴突再生，并改善 PNI 后的功能恢复。重要的是，uPA（尿激酶纤溶酶原激活物）-uPAR（尿激酶纤溶酶原激活物受体）被确定为 IL4 刺激的巨噬细胞促进轴突再生作用的中心轴。IL4 刺激的巨噬细胞分泌 uPA，其抑制作用消除了它们的轴突再生作用。受伤但未受损的轴突表达 uPAR，对 uPA 敏感。这些结果揭示了巨噬细胞相关轴突再生的细胞和分子机制，并为 PNI 的新型治疗提供了基础。
