Background and Purpose: Spinal cord injury (SCI) manifests as a central nervous system disorder causing sensory and motor impairments. Preventing an overabundance of microglial activation is crucial in managing SCI. SIRT1 as a NAD-dependent deacetylase has the effect of ameliorating SCI, but its mechanism of action in microglia activation is still poorly understood. The objective of this research was to explore the role and process of SIRT1 in activating microglia during SCI. Methods: Laminectomy was conducted on the thoracic T10 region of rats, followed by striking the revealed spinal cord using an IH-0400 spinal cord impactor to create a model for SCI animals (n = 30). To create a model of BV2 inflammation, BV2 cells underwent a 24 h treatment with 1 μg/mL LPS. The expression of related proteins was detected by Western blot. Immunofluorescence staining, HE staining and Nissl staining were used to evaluate BV2 cell activation and spinal cord tissue injury in rats. Results: The research indicated minimal expression of SIRT1 in SCI cases, with its heightened expression ameliorating pathological damage and boosting neuron survival rates in SCI rats. Conversely, treatment with LPS markedly reduced autophagy in BV2 cells. Elevated levels of SIRT1 enhanced the production of autophagy-associated proteins LC3-II/I and Beclin1, reduced p62 expression, and curtailed the expression of the activation indicator IBA-1 in BV2 cells. Mechanistically, overexpression of SIRT1 inhibits the expression of TRIB3 by inhibiting Smad3 nuclear metastasis, thereby activating autophagy, inhibiting microglial overactivation and alleviating the development of SCI. Conclusion: Enhancing SIRT1 expression could reduce SCI progression by curbing the overactivation of microglia.
References
[1]
Li, K., Liu, Z., Wu, P., Chen, S., Wang, M., Liu, W., et al. (2023) Micro Electrical Fields Induced MSC-sEVs Attenuate Neuronal Cell Apoptosis by Activating Autophagy via lncRNA MALAT1/miR-22-3p/SIRT1/AMPK Axis in Spinal Cord Injury. JournalofNanobiotechnology, 21, Article No. 451. https://doi.org/10.1186/s12951-023-02217-2
[2]
Quadri, S.A., Farooqui, M., Ikram, A., Zafar, A., Khan, M.A., Suriya, S.S., etal. (2018) Recent Update on Basic Mechanisms of Spinal Cord Injury. NeurosurgicalReview, 43, 425-441. https://doi.org/10.1007/s10143-018-1008-3
[3]
Kirshblum, S., Snider, B., Eren, F. and Guest, J. (2021) Characterizing Natural Recovery after Traumatic Spinal Cord Injury. JournalofNeurotrauma, 38, 1267-1284. https://doi.org/10.1089/neu.2020.7473
[4]
Li, Y., Gu, R., Zhu, Q. and Liu, J. (2018) Changes of Spinal Edema and Expression of Aquaporin 4 in Methylprednisolone-Treated Rats with Spinal Cord Injury. Annals of Clinical & Laboratory Science, 48, 453-459.
Kettenmann, H., Hanisch, U., Noda, M. and Verkhratsky, A. (2011) Physiology of Microglia. PhysiologicalReviews, 91, 461-553. https://doi.org/10.1152/physrev.00011.2010
[7]
Nimmerjahn, A., Kirchhoff, F. and Helmchen, F. (2005) Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in vivo. Science, 308, 1314-1318. https://doi.org/10.1126/science.1110647
[8]
Zhang, Y., Deng, Q., Hong, H., Qian, Z., Wan, B. and Xia, M. (2024) Caffeic Acid Phenethyl Ester Inhibits Neuro-Inflammation and Oxidative Stress Following Spinal Cord Injury by Mitigating Mitochondrial Dysfunction via the SIRT1/PGC1α/DRP1 Signaling Pathway. JournalofTranslationalMedicine, 22, Article No. 304. https://doi.org/10.1186/s12967-024-05089-8
[9]
Li, Y., Lei, Z., Ritzel, R.M., He, J., Li, H., Choi, H.M.C., et al. (2022) Impairment of Autophagy after Spinal Cord Injury Potentiates Neuroinflammation and Motor Function Deficit in Mice. Theranostics, 12, 5364-5388. https://doi.org/10.7150/thno.72713
[10]
Liao, H., Wang, Z., Ran, R., Zhou, K., Ma, C. and Zhang, H. (2021) Biological Functions and Therapeutic Potential of Autophagy in Spinal Cord Injury. FrontiersinCellandDevelopmentalBiology, 9, Article 761273. https://doi.org/10.3389/fcell.2021.761273
[11]
Kim, K.H. and Lee, M. (2014) Autophagy—A Key Player in Cellular and Body Metabolism. NatureReviewsEndocrinology, 10, 322-337. https://doi.org/10.1038/nrendo.2014.35
[12]
Li, W., Yao, S., Li, H., Meng, Z. and Sun, X. (2019) Curcumin Promotes Functional Recovery and Inhibits Neuronal Apoptosis after Spinal Cord Injury through the Modulation of Autophagy. TheJournalofSpinalCordMedicine, 44, 37-45. https://doi.org/10.1080/10790268.2019.1616147
[13]
Chen, H., Ji, H., Zhang, M., Liu, Z., Lao, L., Deng, C., et al. (2017) An Agonist of the Protective Factor Sirt1 Improves Functional Recovery and Promotes Neuronal Survival by Attenuating Inflammation after Spinal Cord Injury. TheJournalofNeuroscience, 37, 2916-2930. https://doi.org/10.1523/jneurosci.3046-16.2017
[14]
Li, B., Li, W., Zheng, M., Wang, Y., Diao, Y., Mou, X., etal. (2023) Corilagin Alleviates Intestinal Ischemia/Reperfusion Injury by Relieving Oxidative Stress and Apoptosis via AMPK/Sirt1-Autophagy Pathway. ExperimentalBiologyandMedicine, 248, 317-326. https://doi.org/10.1177/15353702221147560
[15]
Chen, Q., Zeng, Y., Yang, X., Wu, Y., Zhang, S., Huang, S., et al. (2022) Resveratrol Ameliorates Myocardial Fibrosis by Regulating Sirt1/Smad3 Deacetylation Pathway in Rat Model with Dilated Cardiomyopathy. BMCCardiovascularDisorders, 22, Article No. 17. https://doi.org/10.1186/s12872-021-02401-y
[16]
Chien, L., Deng, J., Jiang, W., Chou, Y., Lin, J. and Huang, G. (2023) Evaluation of Lung Protection of Sanghuangporus Sanghuang through TLR4/NF-κB/MAPK, Keap1/Nrf2/HO-1, CaMKK/AMPK/Sirt1, and TGF-β/SMAD3 Signaling Pathways Mediating Apoptosis and Autophagy. Biomedicine & Pharmacotherapy, 165, Article 115080. https://doi.org/10.1016/j.biopha.2023.115080
[17]
Yang, C., Chen, X., Li, Z., Wu, H., Jing, K., Huang, X., etal. (2020) SMAD3 Promotes Autophagy Dysregulation by Triggering Lysosome Depletion in Tubular Epithelial Cells in Diabetic Nephropathy. Autophagy, 17, 2325-2344. https://doi.org/10.1080/15548627.2020.1824694
[18]
Zhu, J., Fu, Y. and Tu, G. (2020) Role of Smad3 Inhibitor and the Pyroptosis Pathway in Spinal Cord Injury. ExperimentalandTherapeuticMedicine, 20, 1675-1681. https://doi.org/10.3892/etm.2020.8832
[19]
Zhu, P., Xue, J., Zhang, Z., Jia, Y., Tong, Y., Han, D., etal. (2017) Helicobacter pylori VacA Induces Autophagic Cell Death in Gastric Epithelial Cells via the Endoplasmic Reticulum Stress Pathway. CellDeath&Disease, 8, Article No. 3207. https://doi.org/10.1038/s41419-017-0011-x
[20]
Tang, Z., Chen, H., Zhong, D., Wei, W., Liu, L., Duan, Q., etal. (2020) TRIB3 Facilitates Glioblastoma Progression via Restraining Autophagy. Aging, 12, 25020-25034. https://doi.org/10.18632/aging.103969
[21]
Gao, T., Li, J., Cheng, T., Wang, X., Wang, M., Xu, Z., et al. (2024) Ovarian Cancer-Derived TGF-β1 Induces Cancer-Associated Adipocytes Formation by Activating SMAD3/TRIB3 Pathway to Establish Pre-Metastatic Niche. CellDeath&Disease, 15, Article No. 930. https://doi.org/10.1038/s41419-024-07311-3
[22]
Liu, H., Liang, C., Liu, H., Liang, P. and Cheng, H. (2024) MiR-10b-5p Attenuates Spinal Cord Injury and Alleviates LPS-Induced PC12 Cells Injury by Inhibiting TGF-β1 Decay and Activating TGF-β1/Smad3 Pathway through PTBP1. EuropeanJournalofMedicalResearch, 29, Article No. 554. https://doi.org/10.1186/s40001-024-02133-7
[23]
Wang, C., Wang, Q., Lou, Y., Xu, J., Feng, Z., Chen, Y., et al. (2017) Salidroside Attenuates Neuroinflammation and Improves Functional Recovery after Spinal Cord Injury through Microglia Polarization Regulation. JournalofCellularandMolecularMedicine, 22, 1148-1166. https://doi.org/10.1111/jcmm.13368
[24]
Wang, M., Yang, L., Yang, J. and Wang, C. (2019) Shen Shuai IIRecipe Attenuates Renal Injury and Fibrosis in Chronic Kidney Disease by Regulating NLRP3 Inflammasome and Sirt1/smad3 Deacetylation Pathway. BMCComplementaryandAlternativeMedicine, 19, Article No. 107. https://doi.org/10.1186/s12906-019-2524-6
[25]
Russo, G.S., Mangan, J.J., Galetta, M.S., Boody, B., Bronson, W., Segar, A., et al. (2020) Update on Spinal Cord Injury Management. ClinicalSpineSurgery: ASpinePublication, 33, 258-264. https://doi.org/10.1097/bsd.0000000000000956
[26]
Cattelan, A., Ceolotto, G., Bova, S., Albiero, M., Kuppusamy, M., De Martin, S., etal. (2015) NAD+-Dependent SIRT1 Deactivation Has a Key Role on Ischemia-Reperfusion-Induced Apoptosis. VascularPharmacology, 70, 35-44. https://doi.org/10.1016/j.vph.2015.02.004
[27]
Mei, Z., Huang, Y., Feng, Z., Luo, Y., Yang, S., Du, L., et al. (2020) Electroacupuncture Ameliorates Cerebral Ischemia/Reperfusion Injury by Suppressing Autophagy via the SIRT1-FOXO1 Signaling Pathway. Aging, 12, 13187-13205. https://doi.org/10.18632/aging.103420
[28]
Chen, J. and Qin, R. (2020) MicroRNA-138-5p Regulates the Development of Spinal Cord Injury by Targeting SIRT1. MolecularMedicineReports, 22, 328-336. https://doi.org/10.3892/mmr.2020.11071
[29]
Chen, H., Xing, R., Yin, X. and Huang, H. (2023) Activation of SIRT1 by Hyperbaric Oxygenation Promotes Recovery of Motor Dysfunction in Spinal Cord Injury Rats. InternationalJournalofNeuroscience, 135, 52-62. https://doi.org/10.1080/00207454.2023.2285707
[30]
Ma, H., Wang, C., Han, L., Kong, F., Liu, Z., Zhang, B., et al. (2023) Tofacitinib Promotes Functional Recovery after Spinal Cord Injury by Regulating Microglial Polarization via JAK/STAT Signaling Pathway. InternationalJournalofBiologicalSciences, 19, 4865-4882. https://doi.org/10.7150/ijbs.84564
[31]
Hellenbrand, D.J., Quinn, C.M., Piper, Z.J., Elder, R.T., Mishra, R.R., Marti, T.L., etal. (2023) The Secondary Injury Cascade after Spinal Cord Injury: An Analysis of Local Cytokine/Chemokine Regulation. NeuralRegenerationResearch, 19, 1308-1317. https://doi.org/10.4103/1673-5374.385849
[32]
Maki, S., Furuya, T., Inoue, T., Yunde, A., Miura, M., Shiratani, Y., et al. (2024) Machine Learning Web Application for Predicting Functional Outcomes in Patients with Traumatic Spinal Cord Injury Following Inpatient Rehabilitation. JournalofNeurotrauma, 41, 1089-1100. https://doi.org/10.1089/neu.2022.0383
[33]
Dai, C., Qu, B., Peng, B., Liu, B., Li, Y., Niu, C., et al. (2023) Phosphoglycerate Mutase 5 Facilitates Mitochondrial Dysfunction and Neuroinflammation in Spinal Tissues after Spinal Cord Injury. InternationalImmunopharmacology, 116, Article 109773. https://doi.org/10.1016/j.intimp.2023.109773
[34]
Patil, V., Bohara, R., Winter, C., Kilcoyne, M., McMahon, S. and Pandit, A. (2022) An Insight into New Glycotherapeutics in Glial Inflammation: Understanding the Role of Glycosylation in Mitochondrial Function and Acute to the Chronic Phases of Inflammation. CNSNeuroscience&Therapeutics, 29, 429-444. https://doi.org/10.1111/cns.14016
[35]
Wu, C., Wang, L., Chen, S., Shi, L., Liu, M., Tu, P., et al. (2023) Iron Induces B Cell Pyroptosis through Tom20-Bax-Caspase-Gasdermin E Signaling to Promote Inflammation Post-Spinal Cord Injury. JournalofNeuroinflammation, 20, Article No. 171. https://doi.org/10.1186/s12974-023-02848-0
[36]
Jiang, J., Xu, L., Yang, L., Liu, S. and Wang, Z. (2023) Mitochondrial-Derived Peptide Mots-C Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice by Inhibiting Microglia Activation and Neuronal Oxidative Damage in the Spinal Cord via the AMPK Pathway. ACSChemicalNeuroscience, 14, 2362-2374. https://doi.org/10.1021/acschemneuro.3c00140
[37]
Lu, P., Han, D., Zhu, K., Jin, M., Mei, X. and Lu, H. (2019) Effects of Sirtuin 1 on Microglia in Spinal Cord Injury: Involvement of Wnt/β-Catenin Signaling Pathway. NeuroReport, 30, 867-874. https://doi.org/10.1097/wnr.0000000000001293
[38]
Chen, S., Ye, J., Wu, G., Shi, J., Li, X., Chen, X., et al. (2023) Histone Deacetylase 3 Inhibition Ameliorates Microglia-Mediated Neuro-Inflammation via the SIRT1/Nrf2 Pathway after Traumatic Spinal Cord Injury. NeurorehabilitationandNeuralRepair, 37, 503-518. https://doi.org/10.1177/15459683231183716
[39]
Li, J., Cheng, X., Fu, D., Liang, Y., Chen, C., Deng, W., et al. (2022) Autophagy of Spinal Microglia Affects the Activation of Microglia through the PI3K/AKT/mTOR Signaling Pathway. Neuroscience, 482, 77-86. https://doi.org/10.1016/j.neuroscience.2021.12.005
[40]
Chen, K., Chen, W., Liu, S.L., Wu, T.S., Yu, K.F., Qi, J., etal. (2018) Epigallocatechingallate Attenuates Myocardial Injury in a Mouse Model of Heart Failure through TGF-β1/Smad3 Signaling Pathway. MolecularMedicineReports, 17, 7652-7660. https://doi.org/10.3892/mmr.2018.8825
[41]
Li, F., Liu, H., Zhang, K., Xiao, D., Wang, C. and Wang, Y. (2021) Adipose-Derived Stromal Cells Improve Functional Recovery after Spinal Cord Injury through TGF-β1/Smad3/PLOD2 Pathway Activation. Aging, 13, 4370-4387. https://doi.org/10.18632/aging.202399
[42]
Lu, Y., Fang, Y., Wang, S., Guo, J., Song, J., Zhu, L., etal. (2024) Cepharanthine Sensitizes Gastric Cancer Cells to Chemotherapy by Targeting TRIB3-FOXO3-FOXM1 Axis to Inhibit Autophagy. Phytomedicine, 135, Article 156161. https://doi.org/10.1016/j.phymed.2024.156161
[43]
Hua, F., Li, K., Yu, J. and Hu, Z. (2015) The TRIB3-SQSTM1 Interaction Mediates Metabolic Stress-Promoted Tumorigenesis and Progression via Suppressing Autophagic and Proteasomal Degradation. Autophagy, 11, 1929-1931. https://doi.org/10.1080/15548627.2015.1084458
