Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury
Xuhui Ge,
Pengyu Tang,
Yuluo Rong,
Dongdong Jiang,
Xiao Lu,
Chengyue Ji,
Jiaxing Wang,
Chenyu Huang,
Ao Duan,
Yang Liu,
Xinglin Chen,
Xichen Chen,
Zhiyang Xu,
Feng Wang,
Zibin Wang,
Xiaoyan Li,
Wene Zhao,
Jin Fan,
Wei Liu,
Guoyong Yin,
Weihua Cai
Affiliations
Xuhui Ge
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
Pengyu Tang
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
Yuluo Rong
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
Dongdong Jiang
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
Xiao Lu
Department of Orthopedics, Dongtai Hospital Affiliated to Nantong University, Yancheng, 224200, Jiangsu, China
Chengyue Ji
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
Jiaxing Wang
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
Chenyu Huang
Department of Orthopedics, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China
Ao Duan
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
Yang Liu
Department of Orthopedics, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, 214002, Jiangsu, China
Xinglin Chen
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
Xichen Chen
Department of Analytical & Testing Center, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
Zhiyang Xu
Department of Analytical & Testing Center, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
Feng Wang
Department of Analytical & Testing Center, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
Zibin Wang
Department of Analytical & Testing Center, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
Xiaoyan Li
Department of Analytical & Testing Center, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
Wene Zhao
Department of Analytical & Testing Center, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
Jin Fan
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
Wei Liu
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China; Corresponding author.
Guoyong Yin
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China; Corresponding author.
Weihua Cai
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China; Corresponding author.
Pathologically, blood-spinal-cord-barrier (BSCB) disruption after spinal cord injury (SCI) leads to infiltration of numerous peripheral macrophages into injured areas and accumulation around newborn vessels. Among the leaked macrophages, M1-polarized macrophages are dominant and play a crucial role throughout the whole SCI process. The aim of our study was to investigate the effects of M1-polarized bone marrow-derived macrophages (M1-BMDMs) on vascular endothelial cells and their underlying mechanism. Microvascular endothelial cell line bEnd.3 cells were treated with conditioned medium or exosomes derived from M1-BMDMs, followed by evaluations of endothelial-to-mesenchymal transition (EndoMT) and mitochondrial function. After administration, we found conditioned medium or exosomes from M1-BMDMs significantly promoted EndoMT of vascular endothelial cells in vitro and in vivo, which aggravated BSCB disruption after SCI. In addition, significant dysfunction of mitochondria and accumulation of reactive oxygen species (ROS) were also detected. Furthermore, bioinformatics analysis demonstrated that miR-155 is upregulated in both M1-polarized macrophages and microglia. Experimentally, exosomal transfer of miR-155 participated in M1-BMDMs-induced EndoMT and mitochondrial ROS generation in bEnd.3 cells, and subsequently activated the NF-κB signaling pathway by targeting downstream suppressor of cytokine signaling 6 (SOCS6), and suppressing SOCS6-mediated p65 ubiquitination and degradation. Finally, a series of rescue assay further verified that exosomal miR155/SOCS6/p65 axis regulated the EndoMT process and mitochondrial function in vascular endothelial cells. In summary, our work revealed a potential mechanism describing the communications between macrophages and vascular endothelial cells after SCI which could benefit for future research and aid in the development of potential therapies for SCI.
