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Silencing TAK1 reduces MAPKs-MMP2/9 expression to reduce inflammation-driven neurohistological disruption post spinal
Shuai Jiang1, Yandan Wu2, Shunjie Wu1
1Spine Center, Zhongda Hospital of Southeast University, Nanjing, China.
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.
Insights
Transforming growth factor-β-activated kinase 1 (TAK1) inhibition reduces neuroinflammation after spinal cord injury (SCI). This study shows TAK1 inhibition lessens microglia activation and improves locomotor recovery, offering a potential therapeutic strategy for SCI.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Microglia activation and inflammatory metabolite accumulation exacerbate neurological damage following spinal cord injury (SCI).
- The mitogen-activated protein kinases (MAPKs) pathway is crucial in mediating microglia inflammatory responses.
- Transforming growth factor-β-activated kinase 1 (TAK1) acts as a key regulator upstream of the MAPKs signaling pathway.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting TAK1 in mitigating neuroinflammation post-SCI.
- To elucidate the role of the TAK1/MAPKs axis in microglia activation and its impact on SCI outcomes.
Main Methods:
- In vitro: BV2 microglia cell line stimulated with lipopolysaccharide (LPS) and treated with TAK1 inhibitor 5Z-7-Oxozeaenol (ZO).
- In vivo: Adult male mice subjected to mechanical SCI and treated with ZO via intraperitoneal injection.
- Assessed inflammatory markers, cell migration, matrix metalloproteinase (MMP) 2/9 production, MAPKs activation, tissue damage, and locomotor recovery.
Main Results:
- In vitro, ZO treatment significantly reduced LPS-induced inflammatory markers, cell migration, and MMP2/9 production in microglia.
- ZO treatment decreased MAPKs pathway activation, suggesting modulation via the TAK1/MAPKs axis.
- In vivo, ZO-treated mice showed reduced microglia pro-inflammatory activation, decreased MMP2/9 expression, less tissue damage, and improved locomotor function compared to SCI controls.
Conclusions:
- TAK1 inhibition effectively impedes microglia activation, enzymatic synthesis, and migration in the early phase post-SCI.
- The anti-inflammatory effects of TAK1 inhibition are mediated through the downregulation of the MAPKs pathway.
- TAK1 inhibition represents a potent anti-inflammatory therapeutic strategy for spinal cord injury.
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