2. Academic Validation
  3. Silencing TAK1 reduces MAPKs-MMP2/9 expression to reduce inflammation-driven neurohistological disruption post spinal cord injury

Silencing TAK1 reduces MAPKs-MMP2/9 expression to reduce inflammation-driven neurohistological disruption post spinal cord injury

  • Cell Death Discov. 2021 May 8;7(1):96. doi: 10.1038/s41420-021-00481-5.
Shuai Jiang  # 1,  Yandan Wu  # 2,  Shunjie Wu  # 1,  Suhui Ye 1,  Renyi Kong 3,  Jie Chang 3,  Mingjie Xia 4,  Junping Bao 1,  Xin Peng 1,  Xin Hong 5,  Zhanyang Qian 6,  Haijun Li 7
Affiliations

Affiliations

  • 1 Spine Center, Zhongda Hospital of Southeast University, Nanjing, China.
  • 2 Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing, China.
  • 3 Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 4 Department of Orthopedics, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 5 Spine Center, Zhongda Hospital of Southeast University, Nanjing, China. [email protected].
  • 6 Spine Center, Zhongda Hospital of Southeast University, Nanjing, China. [email protected].
  • 7 Department of Orthopedics, Taizhou Clinical Medical School of Nanjing Medical University, Taizhou People's Hospital, Taizhou, China. [email protected].
  • # Contributed equally.
PMID: 33966042 DOI: 10.1038/s41420-021-00481-5
Abstract

Microglia activation post traumatic spinal cord injury (SCI) provokes accumulation of inflammatory metabolites, leading to increasing neurological disruption. Our previous studies demonstrated that blocking MAPKs pathway mitigated microglia inflammatory activation and prevented cords from neuroinflammation-induced secondary injury. Transforming growth factor-β-activated kinase 1 (TAK1) is an upstream gate regulating activation of MAPKs signaling. To validate the therapeutic effect of TAK1 inhibition in neuroinflammation post SCI, in the current study, cultures of microglia BV2 line was undergone lipopolysaccharide (LPS) stimulation in the presence of TAK1 inhibitor 5Z-7-Oxozeaenol (ZO), LPS, or control. LPS triggered inflammatory level, cell migration, and matrix metalloproteinase (MMP) 2/9 production, which was reduced in ZO-treated cultures. TAK1 inhibition by ZO also decreased activation of MAPKs pathway, indicating that ZO-mediated alleviation of neuroinflammation is likely modulated via TAK1/MAPKs axis. In vivo, neuroinflammatory level and tissue destruction were assessed in adult male mice that were undergone SCI by mechanical trauma, and treated with ZO by intraperitoneal injection. Compared with SCI mice, ZO-treated mice exhibited less microglia pro-inflammatory activation and accumulation adjacent to injured core linked to reduced MMP2/9 expression, leading to minor tissue damage and better locomotor recovery. To sum up, the obtained data proved that in the early phase post SCI, TAK1 inhibition impedes microglia biological activities including activation, enzymatic synthesis, and migration via downregulation of MAPKs pathway, and the effects may be accurately characterized as potent anti-inflammation.

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