Role of Smad3 inhibitor and the pyroptosis pathway in spinal cord injury

Zhu,Jiajun; Fu,Yu; Tu,Guanjun

doi:10.3892/etm.2020.8832

Role of Smad3 inhibitor and the pyroptosis pathway in spinal cord injury

Authors:
- Jiajun Zhu
- Yu Fu
- Guanjun Tu
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Affiliations: Department of Orthopedics, The First Affiliated Hospital of China Medical University, Heping, Shenyang, Liaoning 110000, P.R. China, Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Heping, Shenyang, Liaoning 110004, P.R. China
Published online on: June 3, 2020 https://doi.org/10.3892/etm.2020.8832
Pages: 1675-1681
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to investigate the role of Smad3 inhibitors and the pyroptosis pathway in spinal cord injury, and to determine the underlying mechanism. The pyroptosis signaling pathway may be involved in spinal cord injury during the recovery period. Smad3 inhibitor may serve a role in alleviating spinal cord injury by reducing the pyroptosis of neurons, which is induced by caspase‑1, absent in melanoma‑2 or NOD‑like receptors protein‑1 during the recovery period of spinal cord injury. In the present study, spinal cord injury was alleviated by caspase‑1 and Smad3 inhibitors. Therefore, a Smad3 inhibitor could relieve spinal cord injury in mice by directly downregulating caspase‑1 and reducing neuron pyroptosis following spinal cord injury during the recovery period.

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1	Zhang P, Zhang L, Zhu L, Chen F, Zhou S, Tian T, Zhang Y, Jiang X, Li X, Zhang C, et al: The change tendency of PI3K/Akt pathway after spinal cord injury. Am J Transl Res. 7:2223–2232. 2015.PubMed/NCBI
2	Nori S, Nakamura M and Okano H: Chapter 2. Plasticity and regeneration in the injured spinal cord after cell transplantation therapy. Prog Brain Res. 231:33–56. 2017.PubMed/NCBI View Article : Google Scholar
3	Shi Y and Liu JP: Gdf11 facilitates temporal progression of neurogenesis in the developing spinal cord. J Neurosci. 31:883–893. 2011.PubMed/NCBI View Article : Google Scholar
4	Gokoffski KK, Wu HH, Beites CL, Kim J, Kim EJ, Matzuk MM, Johnson JE, Lander AD and Calof AL: Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate. Development. 138:4131–4142. 2011.PubMed/NCBI View Article : Google Scholar
5	Fink SL and Cookson BT: Apoptosis, pyroptosis, and necrosis: Mechanistic description of dead and dying eukaryotic cells. Infect Immun. 73:1907–1916. 2005.PubMed/NCBI View Article : Google Scholar
6	Miao EA, Rajan JV and Aderem A: Caspase-1-induced pyroptotic cell death. Immunol Rev. 243:206–214. 2011.PubMed/NCBI View Article : Google Scholar
7	Chen L, Liu X, Yu X, Ren R, Wang C, Zhao R, Meng G, Li S and Zhou X: Chlamydia muridarum Infection of Macrophages Stimulates IL-1β Secretion and Cell Death via Activation of Caspase-1 in an RIP3-Independent Manner. BioMed Rese Int. 2017(1592365)2017.PubMed/NCBI View Article : Google Scholar
8	Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C and Nuñez G: Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 3(e111)2007.PubMed/NCBI View Article : Google Scholar
9	Eichholz K, Bru T, Tran TT, Fernandes P, Welles H, Mennechet FJ, Manel N, Alves P, Perreau M and Kremer EJ: Immune-Complexed Adenovirus Induce AIM2-Mediated Pyroptosis in Human Dendritic Cells. PLoS Pathog. 12(e1005871)2016.PubMed/NCBI View Article : Google Scholar
10	Li R, Zhang LM and Sun WB: Erythropoietin rescues primary rat cortical neurons from pyroptosis and apoptosis via Erk1/2-Nrf2/Bach1 signal pathway. Brain Res Bull. 130:236–244. 2017.PubMed/NCBI View Article : Google Scholar
11	Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E and Fitzgerald KA: AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 458:514–518. 2009.PubMed/NCBI View Article : Google Scholar
12	Hu W, Zhang Y, Wu W, Yin Y, Huang D, Wang Y and Li W and Li W: Chronic glucocorticoids exposure enhances neurodegeneration in the frontal cortex and hippocampus via NLRP-1 inflammasome activation in male mice. Brain Behav Immun. 52:58–70. 2016.PubMed/NCBI View Article : Google Scholar
13	Jorgensen I, Lopez JP, Laufer SA and Miao EA: IL-1β, IL-18, and eicosanoids promote neutrophil recruitment to pore-induced intracellular traps following pyroptosis. Eur J Immunol. 46:2761–2766. 2016.PubMed/NCBI View Article : Google Scholar
14	Marques SA, Garcez VF, Del Bel EA and Martinez AM: A simple, inexpensive and easily reproducible model of spinal cord injury in mice: Morphological and functional assessment. J Neurosci Methods. 177:183–193. 2009.PubMed/NCBI View Article : Google Scholar
15	Basso DM, Fisher LC, Anderson AJ, Jakeman LB, McTigue DM and Popovich PG: Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma. 23:635–659. 2006.PubMed/NCBI View Article : Google Scholar
16	Awad F, Assrawi E, Louvrier C, Jumeau C, Georgin-Lavialle S, Grateau G, Amselem S, Giurgea I and Karabina SA: Inflammasome biology, molecular pathology and therapeutic implications. Pharmacol Ther. 187:133–149. 2018.PubMed/NCBI View Article : Google Scholar
17	Winkler S, Hedrich CM and Rösen-Wolff A: Caspase-1 regulates autoinflammation in rheumatic diseases. Z Rheumatol. 75:265–275. 2016.PubMed/NCBI View Article : Google Scholar : (In German).
18	Cai R, Liu L, Luo B, Wang J, Shen J, Shen Y, Zhang R, Chen J and Lu H: Caspase-1 Activity in CD4 T Cells Is Downregulated Following Antiretroviral Therapy for HIV-1 Infection. AIDS Res Hum Retroviruses. 33:164–171. 2017.PubMed/NCBI View Article : Google Scholar
19	de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD and Keane RW: A molecular platform in neurons regulates inflammation after spinal cord injury. J Neurosci. 28:3404–3414. 2008.PubMed/NCBI View Article : Google Scholar
20	Young W: Secondary injury mechanisms in acute spinal cord injury. J Emerg Med. 11 (Suppl 1):13–22. 1993.PubMed/NCBI
21	Oyinbo CA: Secondary injury mechanisms in traumatic spinal cord injury: A nugget of this multiply cascade. Acta Neurobiol Exp (Wars). 71:281–299. 2011.PubMed/NCBI
22	Impellizzeri D, Mazzon E, Paterniti I, Esposito E and Cuzzocrea S: Effect of fasudil, a selective inhibitor of Rho kinase activity, in the secondary injury associated with the experimental model of spinal cord trauma. J Pharmacol Exp Ther. 343:21–33. 2012.PubMed/NCBI View Article : Google Scholar
23	Li M, Ona VO, Chen M, Kaul M, Tenneti L, Zhang X, Stieg PE, Lipton SA and Friedlander RM: Functional role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury. Neuroscience. 99:333–342. 2000.PubMed/NCBI View Article : Google Scholar
24	Rochette L, Zeller M, Cottin Y and Vergely C: Growth and differentiation factor 11 (GDF11): Functions in the regulation of erythropoiesis and cardiac regeneration. Pharmacol Ther. 156:26–33. 2015.PubMed/NCBI View Article : Google Scholar
25	Duran J, Troncoso MF, Lagos D, Ramos S, Marin G and Estrada M: GDF11 Modulates Ca²⁺-Dependent Smad2/3 Signaling to Prevent Cardiomyocyte Hypertrophy. Int J Mol Sci. 19(1508)2018.PubMed/NCBI View Article : Google Scholar
26	Lu Q, Tu ML, Li CJ, Zhang L, Jiang TJ, Liu T and Luo XH: GDF11 Inhibits Bone Formation by Activating Smad2/3 in Bone Marrow Mesenchymal Stem Cells. Calcif Tissue Int. 99:500–509. 2016.PubMed/NCBI View Article : Google Scholar
27	Tamai R and Kiyoura Y: Alendronate augments lipid A-induced IL-1β release and Smad3/NLRP3/ASC-dependent cell death. Life Sci. 198:8–17. 2018.PubMed/NCBI View Article : Google Scholar