Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou Ave North 1838, Guangzhou, 510515, China.
Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou, 510515, China.
J Neuroinflammation. 2021 Oct 15;18(1):234. doi: 10.1186/s12974-021-02292-y.
Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian degeneration, thus creating a conducive microenvironment for nerve regeneration. Recently, drugs targeting the RhoA pathway have been widely used to promote peripheral axonal regeneration. However, the role of RhoA in macrophage during Wallerian degeneration and nerve regeneration after peripheral nerve injury is still unknown. Herein, we come up with the hypothesis that RhoA might influence Wallerian degeneration and nerve regeneration by affecting the migration and phagocytosis of macrophages after peripheral nerve injury.
Immunohistochemistry, Western blotting, H&E staining, and electrophysiology were performed to access the Wallerian degeneration and axonal regeneration after sciatic nerve transection and crush injury in the Lyz; RhoA (cKO) mice or Lyz2 (Cre) mice, regardless of sex. Macrophages' migration and phagocytosis were detected in the injured nerves and the cultured macrophages. Moreover, the expression and potential roles of ROCK and MLCK were also evaluated in the cultured macrophages.
Our findings suggest that RhoA depletion in macrophages exerts a detrimental effect on Wallerian degeneration and nerve regeneration, which is most likely due to the impaired migration and phagocytosis of macrophages resulted from disrupted RhoA/ROCK/MLCK pathway. Since previous research has proved RhoA inhibition in neurons was favoring for axonal regeneration, the present study reminds us of that the cellular specificity of RhoA-targeted drugs is needed to be considered in the future application for treating peripheral nerve injury.
大量巨噬细胞被募集到受损的神经中，在 Wallerian 变性过程中发挥关键作用，吞噬变性轴突和髓鞘的碎片，从而为神经再生创造有利的微环境。最近，靶向 RhoA 通路的药物已被广泛用于促进周围轴突再生。然而，RhoA 在巨噬细胞中的作用以及周围神经损伤后神经再生仍然未知。在此，我们提出假设，即 RhoA 可能通过影响周围神经损伤后巨噬细胞的迁移和吞噬作用来影响 Wallerian 变性和神经再生。
通过免疫组织化学、Western blot、H&E 染色和电生理学方法，评估 Lyz;RhoA(cKO) 小鼠或 Lyz2(Cre) 小鼠（不分性别）坐骨神经横断和挤压损伤后的 Wallerian 变性和轴突再生。检测损伤神经和培养巨噬细胞中巨噬细胞的迁移和吞噬作用。此外，还评估了培养巨噬细胞中 ROCK 和 MLCK 的表达及其潜在作用。
我们的研究结果表明，巨噬细胞中 RhoA 的缺失对 Wallerian 变性和神经再生有不利影响，这很可能是由于 RhoA/ROCK/MLCK 通路破坏导致巨噬细胞迁移和吞噬作用受损所致。由于先前的研究已经证明神经元中 RhoA 的抑制有利于轴突再生，因此本研究提醒我们，在未来应用于治疗周围神经损伤时，需要考虑 RhoA 靶向药物的细胞特异性。
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