1. Academic Validation
  2. Blockade of the ADAM8-Fra-1 complex attenuates neuroinflammation by suppressing the Map3k4/MAPKs axis after spinal cord injury

Blockade of the ADAM8-Fra-1 complex attenuates neuroinflammation by suppressing the Map3k4/MAPKs axis after spinal cord injury

  • Cell Mol Biol Lett. 2024 May 16;29(1):75. doi: 10.1186/s11658-024-00589-3.
Zhanyang Qian # 1 2 Rulin Li # 1 3 Tianyu Zhao # 1 3 Kunxin Xie 4 PengFei Li 1 5 Guangshen Li 1 Na Shen 6 Jiamin Gong 6 Xin Hong 2 Lei Yang 7 Haijun Li 8
Affiliations

Affiliations

  • 1 Department of Orthopedics, Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China.
  • 2 Department of Orthopedics, Zhongda Hospital of Southeast University, Nanjing, China.
  • 3 School of Postgraduate, Dalian Medical University, Dalian, China.
  • 4 Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
  • 5 School of Postgraduate, Nanjing University of Chinese Medicine, Nanjing, China.
  • 6 School of Basic Medicine, Nanjing Medical University, Nanjing, China.
  • 7 Department of Orthopedics, Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China. leiyang@njmu.edu.cn.
  • 8 Department of Orthopedics, Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China. 13901436563@139.com.
  • # Contributed equally.
Abstract

Background: Mechanical spinal cord injury (SCI) is a deteriorative neurological disorder, causing secondary neuroinflammation and neuropathy. ADAM8 is thought to be an extracellular metalloproteinase, which regulates proteolysis and cell adherence, but whether its intracellular region is involved in regulating neuroinflammation in microglia after SCI is unclear.

Methods: Using animal tissue RNA-Seq and clinical blood sample examinations, we found that a specific up-regulation of ADAM8 in microglia was associated with inflammation after SCI. In vitro, microglia stimulated by HMGB1, the tail region of ADAM8, promoted microglial inflammation, migration and proliferation by directly interacting with ERKs and Fra-1 to promote activation, then further activated Map3k4/JNKs/p38. Using SCI mice, we used BK-1361, a specific inhibitor of ADAM8, to treat these mice.

Results: The results showed that administration of BK-1361 attenuated the level of neuroinflammation and reduced microglial activation and recruitment by inhibiting the ADAM8/Fra-1 axis. Furthermore, treatment with BK-1361 alleviated glial scar formation, and also preserved myelin and axonal structures. The locomotor recovery of SCI mice treated with BK-1361 was therefore better than those without treatment.

Conclusions: Taken together, the results showed that ADAM8 was a critical molecule, which positively regulated neuroinflammatory development and secondary pathogenesis by promoting microglial activation and migration. Mechanically, ADAM8 formed a complex with ERK and Fra-1 to further activate the Map3k4/JNK/p38 axis in microglia. Inhibition of ADAM8 by treatment with BK-1361 decreased the levels of neuroinflammation, glial formation, and neurohistological loss, leading to favorable improvement in locomotor functional recovery in SCI mice.

Keywords

ADAM8; Fra-1; Map3k4; Microglia; Neuroinflammation; Spinal cord injury.

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