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<p>The persistence of myelin debris after spinal cord injury (SCI) constitutes a formidable barrier to axonal regeneration, remyelination, and functional recovery by initiating inflammatory cascades. Microglia, known for their superior phagocytic and degradative capabilities, are crucial in clearing myelin debris. Yet, the molecular mechanisms governing their function remain elusive. Our previous research has identified a sustained upregulation of Fascin-1, an actin-binding protein essential for phagocytosis, in Cx3cr1<sup>+</sup> microglia after SCI. Here, we reveal that ablation of microglial Fascin-1 exacerbates neuronal loss and hampers motor recovery after SCI, correlating with diminished microglial phagocytic activity in <i>Cx3cr1</i><sup><i>cre+/−</i></sup>;<i>Fascin-1</i><sup><i>fl/fl</i></sup> mice. We demonstrated that dysregulated Fascin-1 phosphorylation impairs microglial phagocytosis, linked to the upstream Mas1/Protein kinase C gamma (PKCγ) axis. Pharmacologic activation of the Mas1/PKC axis to drive Fascin-1 phosphorylation in microglia restores phagocytic function, thereby alleviating neuronal loss and facilitating neurological recovery after SCI. Our findings underscore the critical role of Fascin-1 phosphorylation in microglial phagocytosis and highlight the Mas1/PKCγ axis as a promising therapeutic target for SCI.</p>

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Dynamic phosphorylation of Fascin-1 orchestrates microglial phagocytosis and neurological recovery after spinal cord injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月25日

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  • Yanchang Liu,
  • Fei Yao,
  • Ziyu Li,
  • Yan Jiang,
  • Jianjian Li,
  • Shuisheng Yu,
  • Xuyang Hu,
  • Fangru Ouyang,
  • Meige Zheng,
  • Li Cheng,
  • Juehua Jing

摘要

The persistence of myelin debris after spinal cord injury (SCI) constitutes a formidable barrier to axonal regeneration, remyelination, and functional recovery by initiating inflammatory cascades. Microglia, known for their superior phagocytic and degradative capabilities, are crucial in clearing myelin debris. Yet, the molecular mechanisms governing their function remain elusive. Our previous research has identified a sustained upregulation of Fascin-1, an actin-binding protein essential for phagocytosis, in Cx3cr1+ microglia after SCI. Here, we reveal that ablation of microglial Fascin-1 exacerbates neuronal loss and hampers motor recovery after SCI, correlating with diminished microglial phagocytic activity in Cx3cr1cre+/−;Fascin-1fl/fl mice. We demonstrated that dysregulated Fascin-1 phosphorylation impairs microglial phagocytosis, linked to the upstream Mas1/Protein kinase C gamma (PKCγ) axis. Pharmacologic activation of the Mas1/PKC axis to drive Fascin-1 phosphorylation in microglia restores phagocytic function, thereby alleviating neuronal loss and facilitating neurological recovery after SCI. Our findings underscore the critical role of Fascin-1 phosphorylation in microglial phagocytosis and highlight the Mas1/PKCγ axis as a promising therapeutic target for SCI.