Zhang Chenxi, Zhao Shujie, Huang Zhenfei, Xue Ao, Liu Hao, Dai Siming, Zheng Ziyang, Li Yin, Guo Xiaodong, Gu Jun, Zhang Feng, Wang Fubing, Wang Yongxiang, Zhou Xiaohua, Zhang Shujun, Zhang Hanwen, Shen Jun, Chen Jian, Yin Guoyong
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China; Department of Orthopedics, Suzhou Municipal Hospital, Nanjing Medical University, Jiangsu, Suzhou, 215000, China.
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China.
Redox Biol. 2025 Feb;79:103469. doi: 10.1016/j.redox.2024.103469. Epub 2024 Dec 12.
After spinal cord injury (SCI), phagocytes endocytose myelin debris to form foam cells, exacerbating the inflammatory response. It has been previously shown that macrophages become foam cells through the phagocytosis of myelin debris via receptor-dependent mechanisms after SCI. Blocking receptor-mediated endocytosis did not completely prevent foam cell formation, so we investigated receptor-independent endocytosis. Here, we revealed that foam cells formed after myelin debris internalization were predominantly macrophages rather than microglia. Receptor-independent macropinocytosis has an important position in foamy macrophage formation through engagement of myelin debris endocytosis after SCI. Mechanistic studies showed that cholesterol crystallization following macropinocytosis-mediated foamy macrophage formation promoted the reactive oxygen species (ROS) production and the NOD-like receptor protein 3 (NLRP3) inflammasome activation, increasing the secretion of interleukin-1β (IL-1β). Inhibition of macropinocytosis might reverse this effect, resulting in enhanced axonal regeneration and reduced neural apoptosis, thereby improving outcomes after SCI. Overall, our study revealed a previously unrecognized role for macropinocytosis in foamy macrophages formation after SCI, and confer a promising therapeutic strategy for SCI through focus on macropinocytosis.
脊髓损伤（SCI）后，吞噬细胞通过胞吞作用摄取髓磷脂碎片形成泡沫细胞，从而加剧炎症反应。先前的研究表明，脊髓损伤后巨噬细胞通过受体依赖性机制吞噬髓磷脂碎片而成为泡沫细胞。阻断受体介导的内吞作用并不能完全阻止泡沫细胞的形成，因此我们研究了非受体依赖性内吞作用。在这里，我们发现髓磷脂碎片内化后形成的泡沫细胞主要是巨噬细胞而非小胶质细胞。非受体依赖性巨吞饮作用在脊髓损伤后通过参与髓磷脂碎片内吞作用在泡沫状巨噬细胞形成中具有重要地位。机制研究表明，巨吞饮作用介导的泡沫状巨噬细胞形成后胆固醇结晶促进了活性氧（ROS）的产生和NOD样受体蛋白3（NLRP3）炎性小体的激活，增加了白细胞介素-1β（IL-1β）的分泌。抑制巨吞饮作用可能会逆转这种效应，从而促进轴突再生并减少神经细胞凋亡，进而改善脊髓损伤后的预后。总体而言，我们的研究揭示了巨吞饮作用在脊髓损伤后泡沫状巨噬细胞形成中以前未被认识的作用，并通过关注巨吞饮作用为脊髓损伤提供了一种有前景的治疗策略。
