IL4 stimulated macrophages promote axon regeneration after peripheral nerve injury by secreting uPA to stimulate uPAR upregulated in injured axons
IL4 stimulated macrophages promote axon regeneration after peripheral nerve injury by secreting uPA to stimulate uPAR upregulated in injured axons
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DOI：
10.1007/s00018-022-04310-5
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发表时间：
2022-06-01
影响因子：
8
通讯作者：
Iwasaki, Norimasa
中科院分区：
文献类型：
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作者：
Matsui, Yuki;Kadoya, Ken;Iwasaki, Norimasa
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然是未知的。在这里，目前的研究表明，典型的M2巨噬细胞，这是由IL 4模拟产生的，有能力刺激轴突生长的直接作用于轴突和移植的IL 4刺激的巨噬细胞到沃勒变性的区域增强轴突再生和改善功能恢复后PNI。重要的是，uPA（尿激酶纤溶酶原激活剂）-uPA受体（uPAR）被鉴定为IL 4刺激的巨噬细胞的轴突再生效应的中心轴。IL-4刺激巨噬细胞分泌uPA，抑制uPA可使其轴突再生作用消失。损伤但不完整的轴突表达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的新治疗提供了基础。
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.