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LncRNA UCA1 Suppresses the Inflammation Via Modulating miR-203-Mediated Regulation of MEF2C/NF-κB Signaling Pathway in Epilepsy

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Abstract

Although many advances have been made in the pathogenesis of epilepsy recently, the pathological mechanisms of epilepsy are still largely unknown. Exploring the pathological mechanisms and developing novel therapeutic strategies for epilepsy are urgently needed. A SD rat model of epilepsy was established with lithium chloride-pilocarpine. Astrocytes were isolated, cultured from 8 to 12 week rats and identified by flow cytometry and immunofluorescence. Immunohistochemical staining was used for MEF2C and NF-κB in paraffin-embedded sections. RT-qPCR and western blot were used to analyze gene expression. ELISA was used to analyze the concentration of IL-6, TNF-α and Cox-2. Cells were transfected with pcDNA-MEFC2, sh-MEFC2, pcDNA-UCA1, sh-UCA1, miR-203 mimic or miR-203 inhibitor. Cell viability was assessed by MTT assay. Dual luciferase assay was used to determine the direct interaction of lncRNA UCA1/miR-203 and miR-203/MEF2C. MEF2C was down-regulated and inhibited NF-κB expression and the secretion of IL-6 and TNF-α in epilepsy. LncRNA UCA1 was also down-regulated in epilepsy. LncRNA UCA1 over-expression increased the expression of MEF2C and its knock-down decreased MEF2C expression. Luciferase activity showed lncRNA UCA1 directly targeted miR-203 and miR-203 directly targeted MEF2C. MiR-203 suppressed the expression of MEF2C, and promoted NF-κB, phosphorylated IκB/IKK and inflammatory effectors, which was reversed by MEF2C knock-down. Moreover, lncRNA UCA1 could increase the expression of MEF2C to inhibit NF-κB, phosphorylated IκB/IKK and inflammatory effectors, which was also reversed by miR-203 mimic transfection. LncRNA UCA1 inhibited the inflammation via regulating miR-203 mediated regulation of MEF2C/NF-κB signaling in epilepsy. Our investigation elucidated novel pathological mechanisms and provided potential therapeutic targets for epilepsy.

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References

  1. Devinsky O et al (2018) Epilepsy: nature reviews. Dis Primers 4:18024. https://doi.org/10.1038/nrdp.2018.24

    Article  Google Scholar 

  2. Hui Yin, Y., Ahmad, N. & Makmor-Bakry, M. Pathogenesis of epilepsy: challenges in animal models. Iran J Basic Med Sci 16:1119–1132

    Google Scholar 

  3. Rana A, Musto AE (2018) The role of inflammation in the development of epilepsy. J Neuroinflamm 15:144. https://doi.org/10.1186/s12974-018-1192-7

    Article  CAS  Google Scholar 

  4. Musto AE, Gjorstrup P, Bazan NG (2011) The omega-3 fatty acid-derived neuroprotectin D1 limits hippocampal hyperexcitability and seizure susceptibility in kindling epileptogenesis. Epilepsia 52:1601–1608. https://doi.org/10.1111/j.1528-1167.2011.03081.x

    Article  CAS  PubMed  Google Scholar 

  5. Musto AE et al (2016) Dysfunctional epileptic neuronal circuits and dysmorphic dendritic spines are mitigated by platelet-activating factor receptor antagonism. Sci Rep 6:30298. https://doi.org/10.1038/srep30298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Borlot F, Whitney R, Cohn RD, Weiss SK (2019) MEF2C-related epilepsy: Delineating the phenotypic spectrum from a novel mutation and literature review. Seizure 67:86–90. https://doi.org/10.1016/j.seizure.2019.03.015

    Article  PubMed  Google Scholar 

  7. Xu Z et al (2015) Transcription factor MEF2C suppresses endothelial cell inflammation via regulation of NF-kappaB and KLF2. J Cell Physiol 230:1310–1320. https://doi.org/10.1002/jcp.24870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dhanoa JK, Sethi RS, Verma R, Arora JS, Mukhopadhyay CS (2018) Long non-coding RNA: its evolutionary relics and biological implications in mammals: a review. J Anim Sci Technol 60:25. https://doi.org/10.1186/s40781-018-0183-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Batista PJ, Chang HY (2013) Long noncoding RNAs: cellular address codes in development and disease. Cell 152:1298–1307. https://doi.org/10.1016/j.cell.2013.02.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Geng JF et al (2018) LncRNA UCA1 inhibits epilepsy and seizure-induced brain injury by regulating miR-495/Nrf2-ARE signal pathway. Int J Biochem cell Biol 99:133–139. https://doi.org/10.1016/j.biocel.2018.03.021

    Article  CAS  PubMed  Google Scholar 

  11. Lee ST et al (2017) Inhibition of miR-203 reduces spontaneous recurrent seizures in rats. Mol Neurobiol 54:3300–3308. https://doi.org/10.1007/s12035-016-9901-7

    Article  CAS  PubMed  Google Scholar 

  12. Luo W et al (2014) The transient expression of miR-203 and its inhibiting effects on skeletal muscle cell proliferation and differentiation. Cell Death Dis 5:e1347. https://doi.org/10.1038/cddis.2014.289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gong P et al (2018) LncRNA UCA1 promotes tumor metastasis by inducing miR-203/ZEB2 axis in gastric cancer. Cell Death Dis 9:1158. https://doi.org/10.1038/s41419-018-1170-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Grolla AA et al (2013) Amyloid-beta and Alzheimer's disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions. Cell Death Dis 4:e623. https://doi.org/10.1038/cddis.2013.145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Foo LC et al (2011) Development of a method for the purification and culture of rodent astrocytes. Neuron 71:799–811. https://doi.org/10.1016/j.neuron.2011.07.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bellaver B, Souza DG, Souza DO, Quincozes-Santos A (2017) Hippocampal astrocyte cultures from adult and aged rats reproduce changes in glial functionality observed in the aging brain. Mol Neurobiol 54:2969–2985. https://doi.org/10.1007/s12035-016-9880-8

    Article  CAS  PubMed  Google Scholar 

  17. Liu YX et al (2012) Exposure to 1950-MHz TD-SCDMA electromagnetic fields affects the apoptosis of astrocytes via caspase-3-dependent pathway. PLoS ONE 7:e42332. https://doi.org/10.1371/journal.pone.0042332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Faure JB et al (2013) A comprehensive behavioral evaluation in the lithium-pilocarpine model in rats: effects of carisbamate administration during status epilepticus. Epilepsia 54:1203–1213. https://doi.org/10.1111/epi.12219

    Article  CAS  PubMed  Google Scholar 

  19. Jang Y et al (2018) Dysregulated long non-coding RNAs in the temporal lobe epilepsy mouse model. Seizure 58:110–119. https://doi.org/10.1016/j.seizure.2018.04.010

    Article  PubMed  Google Scholar 

  20. Luo ZH et al (2019) Construction and analysis of a dysregulated lncRNA-associated ceRNA network in a rat model of temporal lobe epilepsy. Seizure 69:105–114. https://doi.org/10.1016/j.seizure.2019.04.010

    Article  PubMed  Google Scholar 

  21. Sun SC (2017) The non-canonical NF-kappaB pathway in immunity and inflammation. Nat Rev Immunol 17:545–558. https://doi.org/10.1038/nri.2017.52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tornatore L, Thotakura AK, Bennett J, Moretti M, Franzoso G (2012) The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. Trends Cell Biol 22:557–566. https://doi.org/10.1016/j.tcb.2012.08.001

    Article  CAS  PubMed  Google Scholar 

  23. Stafstrom, C. E. & Carmant, L. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harbor perspectives in medicine 5, doi:10.1101/cshperspect.a022426 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tang F, Hartz AMS, Bauer B (2017) Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol 8:301. https://doi.org/10.3389/fneur.2017.00301

    Article  PubMed  PubMed Central  Google Scholar 

  25. Vezzani A, Aronica E, Mazarati A, Pittman QJ (2013) Epilepsy and brain inflammation. Exp Neurol 244:11–21. https://doi.org/10.1016/j.expneurol.2011.09.033

    Article  CAS  PubMed  Google Scholar 

  26. Vezzani A, Granata T (2005) Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46:1724–1743. https://doi.org/10.1111/j.1528-1167.2005.00298.x

    Article  CAS  PubMed  Google Scholar 

  27. Seifert G, Carmignoto G, Steinhauser C (2010) Astrocyte dysfunction in epilepsy. Brain Res Rev 63:212–221. https://doi.org/10.1016/j.brainresrev.2009.10.004

    Article  CAS  PubMed  Google Scholar 

  28. Steinhauser C, Seifert G, Bedner P (2012) Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling. Glia 60:1192–1202. https://doi.org/10.1002/glia.22313

    Article  PubMed  Google Scholar 

  29. Shen Y et al (2016) Postnatal activation of TLR4 in astrocytes promotes excitatory synaptogenesis in hippocampal neurons. J Cell Biol 215:719–734. https://doi.org/10.1083/jcb.201605046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cao Q, Liu X, Yang F, Wang H (2018) CB2R induces a protective response for epileptic seizure via the PI3K 110alpha-AKT signaling pathway. Exp Ther Med 16:4784–4790. https://doi.org/10.3892/etm.2018.6788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chiavegato A, Zurolo E, Losi G, Aronica E, Carmignoto G (2014) The inflammatory molecules IL-1beta and HMGB1 can rapidly enhance focal seizure generation in a brain slice model of temporal lobe epilepsy. Front Cell Neurosci 8:155. https://doi.org/10.3389/fncel.2014.00155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sama MA et al (2008) Interleukin-1beta-dependent signaling between astrocytes and neurons depends critically on astrocytic calcineurin/NFAT activity. J Biol Chem 283:21953–21964. https://doi.org/10.1074/jbc.M800148200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Robel S et al (2015) Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci 35:3330–3345. https://doi.org/10.1523/JNEUROSCI.1574-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bellot-Saez A, Kekesi O, Morley JW, Buskila Y (2017) Astrocytic modulation of neuronal excitability through K(+) spatial buffering. Neurosci Biobehav Rev 77:87–97. https://doi.org/10.1016/j.neubiorev.2017.03.002

    Article  CAS  PubMed  Google Scholar 

  35. Dossi E, Vasile F, Rouach N (2018) Human astrocytes in the diseased brain. Brain Res Bull 136:139–156. https://doi.org/10.1016/j.brainresbull.2017.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chen X, Gao B, Ponnusamy M, Lin Z, Liu J (2017) MEF2 signaling and human diseases. Oncotarget 8:112152–112165. https://doi.org/10.18632/oncotarget.22899

    Article  PubMed  PubMed Central  Google Scholar 

  37. Shalizi AK, Bonni A (2005) brawn for brains: the role of MEF2 proteins in the developing nervous system. Curr Top Dev Biol 69:239–266. https://doi.org/10.1016/S0070-2153(05)69009-6

    Article  CAS  PubMed  Google Scholar 

  38. Phan D et al (2005) BOP, a regulator of right ventricular heart development, is a direct transcriptional target of MEF2C in the developing heart. Development 132:2669–2678. https://doi.org/10.1242/dev.01849

    Article  CAS  PubMed  Google Scholar 

  39. Verdaguer E et al (2005) Inhibition of the cdk5/MEF2 pathway is involved in the antiapoptotic properties of calpain inhibitors in cerebellar neurons. Br J Pharmacol 145:1103–1111. https://doi.org/10.1038/sj.bjp.0706280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pon JR, Marra MA (2016) MEF2 transcription factors: developmental regulators and emerging cancer genes. Oncotarget 7:2297–2312. https://doi.org/10.18632/oncotarget.6223

    Article  PubMed  Google Scholar 

  41. Leifer D et al (1993) MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex. Proc Natl Acad Sci USA 90:1546–1550. https://doi.org/10.1073/pnas.90.4.1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Latchney SE, Jiang Y, Petrik DP, Eisch AJ, Hsieh J (2015) Inducible knockout of Mef2a, -c, and -d from nestin-expressing stem/progenitor cells and their progeny unexpectedly uncouples neurogenesis and dendritogenesis in vivo. FASEB J 29:5059–5071. https://doi.org/10.1096/fj.15-275651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee DY et al (2015) Dysregulation of long non-coding RNAs in mouse models of localization-related epilepsy. Biochem Biophys Res Commun 462:433–440. https://doi.org/10.1016/j.bbrc.2015.04.149

    Article  CAS  PubMed  Google Scholar 

  44. Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA (2013) Glia and epilepsy: excitability and inflammation. Trends Neurosci 36:174–184. https://doi.org/10.1016/j.tins.2012.11.008

    Article  CAS  PubMed  Google Scholar 

  45. Jimenez-Mateos EM, Henshall DC (2013) Epilepsy and microRNA. Neuroscience 238:218–229. https://doi.org/10.1016/j.neuroscience.2013.02.027

    Article  CAS  PubMed  Google Scholar 

  46. Primo MN, Bak RO, Schibler B, Mikkelsen JG (2012) Regulation of pro-inflammatory cytokines TNFalpha and IL24 by microRNA-203 in primary keratinocytes. Cytokine 60:741–748. https://doi.org/10.1016/j.cyto.2012.07.031

    Article  CAS  PubMed  Google Scholar 

  47. Wang Y, Dong Q, Gu Y, Groome LJ (2016) Up-regulation of miR-203 expression induces endothelial inflammatory response: Potential role in preeclampsia. Am J Reprod Immunol 76:482–490. https://doi.org/10.1111/aji.12589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the grant from the New Xiangya Talent Project of the Third Xiangya Hospital, Central South University, China (JY201721).

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Authors and Affiliations

  1. Department of Hematology, The Second Xiangya Hospital of Central South University, Changsha, 410011, People’s Republic of China

    Qian Yu

  2. Department of Pediatrics, The Third Xiangya Hospital of Central South University, No.138, Tongzipo Road, Yuelu District, Changsha, 410013, People’s Republic of China

    Meng-Wen Zhao

  3. Department of Neurology, The Third Xiangya Hospital of Central South University, No.138, Tongzipo Road, Yuelu District, Changsha, 410013, People’s Republic of China

    Pu Yang

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Yu, Q., Zhao, MW. & Yang, P. LncRNA UCA1 Suppresses the Inflammation Via Modulating miR-203-Mediated Regulation of MEF2C/NF-κB Signaling Pathway in Epilepsy. Neurochem Res 45, 783–795 (2020). https://doi.org/10.1007/s11064-019-02952-9

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