Macropinocytosis enhances foamy macrophage formation and cholesterol crystallization to activate NLRP3 inflammasome after spinal cord injury
Chenxi Zhang,
Shujie Zhao,
Zhenfei Huang,
Ao Xue,
Hao Liu,
Siming Dai,
Ziyang Zheng,
Yin Li,
Xiaodong Guo,
Jun Gu,
Feng Zhang,
Fubing Wang,
Yongxiang Wang,
Xiaohua Zhou,
Shujun Zhang,
Hanwen Zhang,
Jun Shen,
Jian Chen,
Guoyong Yin
Affiliations
Chenxi Zhang
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
Shujie Zhao
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China
Zhenfei Huang
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China
Ao Xue
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China
Hao Liu
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China
Siming Dai
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China
Ziyang Zheng
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China
Yin Li
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China
Xiaodong Guo
Department of Orthopedics, Wuhan Union Hospital of China, Huazhong University of Science and Technology, Hubei, Wuhan, 430022, China
Jun Gu
Department of Orthopedics, Xishan People's Hospital of Wuxi City, Southeast University, Jiangsu, Wuxi, 21405, China
Feng Zhang
Department of Orthopedics, Xuyi People's Hospital, Yangzhou University, Jiangsu, Xuyi, 211700, China
Fubing Wang
Department of Orthopedics, Xuyi People's Hospital, Yangzhou University, Jiangsu, Xuyi, 211700, China
Yongxiang Wang
Department of Orthopedics, Northern Jiangsu People's Hospital, Nanjing Medical University, Jiangsu, Yangzhou, 225001, China
Xiaohua Zhou
Department of Anesthesia and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China
Shujun Zhang
Department of Orthopedics, Wuxi Ninth Hospital, Suzhou University, Jiangsu, Wuxi, 21405, China
Hanwen Zhang
Department of Pathophysiology, Nanjing Medical University, Jiangsu, Nanjing, 211166, China; Corresponding author.
Jun Shen
Department of Orthopedics, Suzhou Municipal Hospital, Nanjing Medical University, Jiangsu, Suzhou, 215000, China; Corresponding authors.
Jian Chen
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China; Corresponding author.
Guoyong Yin
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, Nanjing, 210029, China; Corresponding authors.
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.
