| Institution: | 1. Department of Orthopedics (Spine Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
School of Pharmacy, and Department of Neurosurgery, The Affiliated Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China;2. Department of Orthopedics (Spine Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China;3. School of Pharmacy, and Department of Neurosurgery, The Affiliated Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China;4. Center for Wound Repair and Regeneration, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China;5. Department of Clinical Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China |
| Abstract: | Aims TANK-binding kinase 1 (TBK1) is involved in regulating the pathological process of a variety of inflammatory diseases in the central nervous system. However, its role and underlying molecular mechanisms in spinal cord injury (SCI) remain largely unknown. Methods We employed the TBK1 inhibitor amlexanox (ALX) to address this question. An in vivo clip-compressive SCI model and in vitro lipopolysaccharide (LPS)-induced astrocyte inflammation model were established to examine the effects of TBK1 inhibition on the expression of proinflammatory cytokines. Results In this study, we found that TBK1 and TBK1-medicated innate immune pathways, such as TBK1/IRF3 and noncanonical NF-κB signaling, were activated in astrocytes and neurons after SCI. Furthermore, inhibition of TBK1 by ALX alleviated neuroinflammation response, reduced the loss of motor neurons, and improved the functional recovery after SCI. Mechanistically, inhibition of TBK1 activity promoted the activation of the noncanonical NF-κB signaling pathway and inhibited p-IRF3 activity in LPS-induced astrocytes, and the TBK1 activity was required for astrocytic activation through yes-associated protein (YAP) signaling after SCI and in LPS-induced astrocytes inflammation model. Conclusion TBK1-medicated innate immune pathway in astrocytes through YAP signaling plays an important role in the pathogenesis of SCI and inhibition of TBK1 may be a potential therapeutic drug for SCI. |
