Effect of VX‑765 on the transcriptome profile of mice spinal cords with acute injury

Chen,Jing; Chen,Yu‑Qing; Wang,Sai‑Nan; Duan,Fei‑Xiang; Shi,Yu‑Jiao; Ding,Shu‑Qin; Hu,Jian‑Guo; Lü,He‑Zuo

doi:10.3892/mmr.2020.11129

Effect of VX‑765 on the transcriptome profile of mice spinal cords with acute injury

Authors:
- Jing Chen
- Yu‑Qing Chen
- Sai‑Nan Wang
- Fei‑Xiang Duan
- Yu‑Jiao Shi
- Shu‑Qin Ding
- Jian‑Guo Hu
- He‑Zuo Lü
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Affiliations: Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
Published online on: May 5, 2020 https://doi.org/10.3892/mmr.2020.11129
Pages: 33-42
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Previous studies have shown that caspase-1 plays an important role in the acute inflammatory response of spinal cord injury (SCI). VX‑765, a novel and irreversible caspase‑1 inhibitor, has been reported to effectively intervene in inflammation. However, the effect of VX‑765 on genome‑wide transcription in acutely injured spinal cords remains unknown. Therefore, in the present study, RNA‑sequencing (RNA‑Seq) was used to analyze the effect of VX‑765 on the local expression of gene transcription 8 h following injury. The differentially expressed genes (DEGs) underwent enrichment analysis of functions and pathways by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. Parallel analysis of western blot confirmed that VX‑765 can effectively inhibit the expression and activation of caspase‑1. RNA‑Seq showed that VX‑765 treatment resulted in 1,137 upregulated and 1,762 downregulated DEGs. These downregulated DEGs and their associated signaling pathways, such as focal adhesion, cytokine‑cytokine receptor interaction, leukocyte transendothelial migration, extracellular matrix‑receptor interaction, phosphatidylinositol 3‑kinase‑protein kinase B, Rap1 and hypoxia inducible factor‑1 signaling pathway, are mainly associated with inflammatory response, local hypoxia, macrophage differentiation, adhesion migration and apoptosis of local cells. This suggests that the application of VX‑765 in the acute phase can improve the local microenvironment of SCI by inhibiting caspase‑1. However, whether VX‑765 can be used as a therapeutic drug for SCI requires further exploration. The sequence data have been deposited into the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra/PRJNA548970).

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1	Friedli L, Rosenzweig ES, Barraud Q, Schubert M, Dominici N, Awai L, Nielson JL, Musienko P, Nout-Lomas Y, Zhong H, et al: Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates. Sci Transl Med. 7:302ra1342015. View Article : Google Scholar : PubMed/NCBI
2	de Rivero Vaccari JP, Dietrich WD and Keane RW: Activation and regulation of cellular inflammasomes: Gaps in our knowledge for central nervous system injury. J Cereb Blood Flow Metab. 34:369–375. 2014. View Article : Google Scholar : PubMed/NCBI
3	Krakauer T: Inflammasomes, autophagy, and cell death: The trinity of innate host defense against intracellular bacteria. Mediators Inflamm. 2019:24712152019. View Article : Google Scholar : PubMed/NCBI
4	Li L, Tang W and Yi F: Role of inflammasome in chronic kidney disease. Adv Exp Med Biol. 1165:407–421. 2019. View Article : Google Scholar : PubMed/NCBI
5	Stack JH, Beaumont K, Larsen PD, Straley KS, Henkel GW, Randle JC and Hoffman HM: IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol. 175:2630–2634. 2005. View Article : Google Scholar : PubMed/NCBI
6	Zhang Y and Zheng Y: Effects and mechanisms of potent caspase-1 inhibitor VX765 treatment on collagen-induced arthritis in mice. Clin Exp Rheumatol. 34:111–118. 2016.PubMed/NCBI
7	Flores J, Noel A, Foveau B, Lynham J, Lecrux C and LeBlanc AC: Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model. Nat Commun. 9:39162018. View Article : Google Scholar : PubMed/NCBI
8	Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J and Vezzani A: Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics. 8:304–315. 2011. View Article : Google Scholar : PubMed/NCBI
9	Wu J, Zhao Z, Kumar A, Lipinski MM, Loane DJ, Stoica BA and Faden AI: Endoplasmic reticulum stress and disrupted neurogenesis in the brain are associated with cognitive impairment and depressive-like behavior after spinal cord injury. J Neurotrauma. 33:1919–1935. 2016. View Article : Google Scholar : PubMed/NCBI
10	Horiuchi H, Oshima Y, Ogata T, Morino T, Matsuda S, Miura H and Imamura T: Evaluation of injured axons using two-photon excited fluorescence microscopy after spinal cord contusion injury in YFP-H line mice. Int J Mol Sci. 16:15785–15799. 2015. View Article : Google Scholar : PubMed/NCBI
11	Galvan MD, Luchetti S, Burgos AM, Nguyen HX, Hooshmand MJ, Hamers FP and Anderson AJ: Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury. J Neurosci. 28:13876–13888. 2008. View Article : Google Scholar : PubMed/NCBI
12	Liu JQ, Yang D and Folz RJ: A novel bronchial ring bioassay for the evaluation of small airway smooth muscle function in mice. Am J Physiol Lung Cell Mol Physiol. 291:L281–L288. 2006. View Article : Google Scholar : PubMed/NCBI
13	Song XY, Zhou FH, Zhong JH, Wu LL and Zhou XF: Knockout of p75(NTR) impairs re-myelination of injured sciatic nerve in mice. J Neurochem. 96:833–842. 2006. View Article : Google Scholar : PubMed/NCBI
14	Mehto S, Jena KK, Nath P and Chauhan S, Kolapalli SP, Das SK, Sahoo PK, Jain A, Taylor GA and Chauhan S: The Crohn's disease risk factor IRGM limits NLRP3 inflammasome activation by impeding its assembly and by mediating its selective autophagy. Mol Cell. 73:429–445.e27. 2019. View Article : Google Scholar : PubMed/NCBI
15	Lin YH, Wu Y, Wang Y, Yao ZF, Tang J, Wang R, Shen L, Ding SQ, Hu JG and Lü HZ: Spatio-temporal expression of Hexokinase-3 in the injured female rat spinal cords. Neurochem Int. 113:23–33. 2018. View Article : Google Scholar : PubMed/NCBI
16	Shi LL, Zhang N, Xie XM, Chen YJ, Wang R, Shen L, Zhou JS, Hu JG and Lü HZ: Transcriptome profile of rat genes in injured spinal cord at different stages by RNA-sequencing. BMC Genomics. 18:1732017. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Martinon F, Burns K and Tschopp J: The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 10:417–426. 2002. View Article : Google Scholar : PubMed/NCBI
19	Latz E, Xiao TS and Stutz A: Activation and regulation of the inflammasomes. Nat Rev Immunol. 13:397–411. 2013. View Article : Google Scholar : PubMed/NCBI
20	Mortezaee K, Khanlarkhani N, Beyer C and Zendedel A: Inflammasome: Its role in traumatic brain and spinal cord injury. J Cell Physiol. 233:5160–5169. 2018. View Article : Google Scholar : PubMed/NCBI
21	Zendedel A, Monnink F, Hassanzadeh G, Zaminy A, Ansar MM, Habib P, Slowik A, Kipp M and Beyer C: Estrogen attenuates local inflammasome expression and activation after spinal cord injury. Mol Neurobiol. 55:1364–1375. 2018. View Article : Google Scholar : PubMed/NCBI
22	Chen K, Deng S, Lu H, Zheng Y, Yang G, Kim D, Cao Q and Wu JQ: RNA-seq characterization of spinal cord injury transcriptome in acute/subacute phases: A resource for understanding the pathology at the systems level. PLoS One. 8:e725672013. View Article : Google Scholar : PubMed/NCBI
23	Huang Q, Wu LY, Wang Y and Zhang XS: GOMA: Functional enrichment analysis tool based on GO modules. Chin J Cancer. 32:195–204. 2013. View Article : Google Scholar : PubMed/NCBI
24	Burridge K: Focal adhesions: A personal perspective on a half century of progress. FEBS J. 284:3355–3361. 2017. View Article : Google Scholar : PubMed/NCBI
25	LaFlamme SE, Mathew-Steiner S, Singh N, Colello-Borges D and Nieves B: Integrin and microtubule crosstalk in the regulation of cellular processes. Cell Mol Life Sci. 75:4177–4185. 2018. View Article : Google Scholar : PubMed/NCBI
26	De Pascalis C and Etienne-Manneville S: Single and collective cell migration: The mechanics of adhesions. Mol Biol Cell. 28:1833–1846. 2017. View Article : Google Scholar : PubMed/NCBI
27	Rabelink TJ, van den Berg BM, Garsen M, Wang G, Elkin M and van der Vlag J: Heparanase: Roles in cell survival, extracellular matrix remodelling and the development of kidney disease. Nat Rev Nephrol. 13:201–212. 2017. View Article : Google Scholar : PubMed/NCBI
28	Bonnans C, Chou J and Werb Z: Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 15:786–801. 2014. View Article : Google Scholar : PubMed/NCBI
29	Yue B: Biology of the extracellular matrix: An overview. J Glaucoma. 23 (8 Suppl 1):S20–S23. 2014. View Article : Google Scholar : PubMed/NCBI
30	Roy S, Rizvi ZA and Awasthi A: Metabolic checkpoints in differentiation of helper T cells in tissue inflammation. Front Immunol. 9:30362019. View Article : Google Scholar : PubMed/NCBI
31	Ridiandries A, Tan JTM and Bursill CA: The role of chemokines in wound healing. Int J Mol Sci. 19(pii): E32172018. View Article : Google Scholar : PubMed/NCBI
32	Wang JG, Williams JC, Davis BK, Jacobson K, Doerschuk CM, Ting JP and Mackman N: Monocytic microparticles activate endothelial cells in an IL-1β-dependent manner. Blood. 118:2366–2374. 2011. View Article : Google Scholar : PubMed/NCBI
33	Prendergast CT and Anderton SM: Immune cell entry to central nervous system-current understanding and prospective therapeutic targets. Endocr Metab Immune Disord Drug Targets. 9:315–327. 2009. View Article : Google Scholar : PubMed/NCBI
34	Shechter R, London A and Schwartz M: Orchestrated leukocyte recruitment to immune-privileged sites: Absolute barriers versus educational gates. Nat Rev Immunol. 13:206–218. 2013. View Article : Google Scholar : PubMed/NCBI
35	Demeestere D, Libert C and Vandenbroucke RE: Clinical implications of leukocyte infiltration at the choroid plexus in (neuro)inflammatory disorders. Drug Discov Today. 20:928–941. 2015. View Article : Google Scholar : PubMed/NCBI
36	Vergadi E, Ieronymaki E, Lyroni K, Vaporidi K and Tsatsanis C: Akt signaling pathway in macrophage activation and M1/M2 polarization. J Immunol. 198:1006–1014. 2017. View Article : Google Scholar : PubMed/NCBI
37	Kim C, Ye F and Ginsberg MH: Regulation of integrin activation. Annu Rev Cell Dev Biol. 27:321–345. 2011. View Article : Google Scholar : PubMed/NCBI
38	Pollan SG, Huang F, Sperger JM, Lang JM, Morrissey C, Cress AE, Chu CY, Bhowmick NA, You S, Freeman MR, et al: Regulation of inside-out β1-integrin activation by CDCP1. Oncogene. 37:2817–2836. 2018. View Article : Google Scholar : PubMed/NCBI
39	Dehne N, Fuhrmann D and Brune B: Hypoxia-inducible factor (HIF) in hormone signaling during health and disease. Cardiovasc Hematol Agents Med Chem. 11:125–135. 2013. View Article : Google Scholar : PubMed/NCBI
40	Risbud MV and Shapiro IM: Notochordal cells in the adult intervertebral disc: New perspective on an old question. Crit Rev Eukaryot Gene Expr. 21:29–41. 2011. View Article : Google Scholar : PubMed/NCBI