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CircHivep2 contributes to microglia activation and inflammation via miR‐181a‐5p/SOCS2 signalling in mice with kainic acid‐induced epileptic seizures

Xiaoying, Gao, Guo, Mian, Jie, Liu, Yanmei, Zhu, Ying, Cui, Shengjie, Shu, Haiyan, Gou, Feixiang, Sun +2 more·2020·Journal of Cellular and Molecular Medicine
DOI 10.1111/jcmm.15894PMC PMC7701587
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Abstract

Epilepsy is a chronic brain disease characterized by recurrent seizures. Circular RNA (circRNA) is a novel family of endogenous non‐coding RNAs that have been proposed to regulate gene expression. However, there is a lack of data on the role of circRNA in epilepsy. In this study, the circRNA profiles were evaluated by microarray analysis. In total, 627 circRNAs were up‐regulated, whereas 892 were down‐regulated in the hippocampus in mice with kainic acid (KA)‐induced epileptic seizures compared with control. The expression of circHivep2 was significantly down‐regulated in hippocampus tissues of mice with KA‐induced epileptic seizures and BV‐2 microglia cells upon KA treatment. Bioinformatics analysis predicted that circHivep2 interacts with miR‐181a‐5p to regulate SOCS2 expression, which was validated using a dual‐luciferase reporter assay. Moreover, overexpression of circHivep2 significantly inhibited KA‐induced microglial activation and the expression of inflammatory factors in vitro, which was blocked by miR‐181a‐5p, whereas circHivep2 knockdown further induced microglia cell activation and the release of pro‐inflammatory proteins in BV‐2 microglia cells after KA treatment. The application of circHivep2+ exosomes derived from adipose‐derived stem cells (ADSCs) exerted significant beneficial effects on the behavioural seizure scores of mice with KA‐induced epilepsy compared to control exosomes. The circHivep2+ exosomes also inhibited microglial activation, the expression of inflammatory factors, and the miR‐181a‐5p/SOCS2 axis in vivo. Our results suggest that circHivep2 regulates microglia activation in the progression of epilepsy by interfering with miR‐181a‐5p to promote SOCS2 expression, indicating that circHivep2 may serve as a therapeutic tool to prevent the development of epilepsy.

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  • SOCS2 is involved in STAT3 pathway activation and can mediate microglial polarization regulation.

    “We identified miR-9-5p binding sites in the 3'-UTR of SOCS2 mRNA (Fig. 5a), which was involved in STAT3 pathway activation and able to mediate microglial polarization regulation [35–37].”

    From Neuron secrete exosomes containing miR-9-5p to promote polarization of M1 microglia in depression (2022) · cites this paper as [36]

    The Results section on microglial activation (page not provided) links the circHivep2/miR-181a-5p/SOCS2 pathway to activation in KA-treated BV-2 cells. It does not assess microglial polarization. The Discussion mentions STAT3 in connection with other pathways and SOCS1/SOCS3, but does not establish that SOCS2 activates STAT3. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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  1. [1]Hammer MF, Sprissler R, Bina RW, et al. Altered expression of signaling pathways regulating neuronal excitability in hippocampal tissue of temporal lobe epilepsy patients with low and high seizure frequency. Epilepsy Res. 2019; 155: 106145. 31195185
  2. [2]Jessberger S, Zhao C, Toni N, Clemenson GD Jr, Li Y, Gage FH. Seizure‐associated, aberrant neurogenesis in adult rats characterized with retrovirus‐mediated cell labeling. J Neurosci. 2007; 27: 9400‐ 9407. 17728453 PMC6673128
  3. [3]Perucca P, Scheffer IE, Kiley M. The management of epilepsy in children and adults. Med J Aust. 2018; 208: 226‐ 233. 29540143
  4. [4]Devinsky O, Vezzani A, O'Brien TJ, et al. Epilepsy. Nat Rev Dis Primers. 2018; 4: 18024. 29722352
  5. [5]Lukawski K, Andres‐Mach M, Czuczwar M, Luszczki JJ, Kruszynski K, Czuczwar SJ. Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies. Pharmacol Rep. 2018; 70: 284‐ 293. 29477036
  6. [6]Pitkanen A, Lukasiuk K. Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol. 2011; 10: 173‐ 186. 21256455
  7. [7]Alyu F, Dikmen M. Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms. Acta Neuropsychiatr. 2017; 29: 1‐ 16. 27692004
  8. [8]Vezzani A, Friedman A, Dingledine RJ. The role of inflammation in epileptogenesis. Neuropharmacology. 2013; 69: 16‐ 24. 22521336 PMC3447120
  9. [9]Chen B, Choi H, Hirsch LJ, et al. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2017; 76: 24‐ 31. 28931473
  10. [10]Hansen CC, Ljung H, Brodtkorb E, Reimers A. Mechanisms underlying aggressive behavior induced by antiepileptic drugs: focus on topiramate, levetiracetam, and perampanel. Behav Neurol. 2018; 2018: 2064027. 30581496 PMC6276511
  11. [11]Hauser RM, Henshall DC, Lubin FD. The epigenetics of epilepsy and its progression. Neuroscientist. 2018; 24: 186‐ 200. 28468530
  12. [12]Kobow K, Blumcke I. Epigenetics in epilepsy. Neurosci Lett. 2018; 667: 40‐ 46. 28111355
  13. [13]Lee WJ, Moon J, Jeon D, et al. Possible epigenetic regulatory effect of dysregulated circular RNAs in epilepsy. PLoS One. 2018; 13: e0209829. 30592747 PMC6310357
  14. [14]Srivastava PK, Bagnati M, Delahaye‐Duriez A, et al. Genome‐wide analysis of differential RNA editing in epilepsy. Genome Res. 2017; 27: 440‐ 450. 28250018 PMC5340971
  15. [15]Tiwari D, Peariso K, Gross C. MicroRNA‐induced silencing in epilepsy: opportunities and challenges for clinical application. Dev Dyn. 2018; 247: 94‐ 110. 28850760 PMC5740004
  16. [16]Jimenez‐Mateos EM, Henshall DC. Epilepsy and microRNA. Neuroscience. 2013; 238: 218‐ 229. 23485811
  17. [17]Hu K, Xie YY, Zhang C, et al. MicroRNA expression profile of the hippocampus in a rat model of temporal lobe epilepsy and miR‐34a‐targeted neuroprotection against hippocampal neurone cell apoptosis post‐status epilepticus. BMC Neurosci. 2012; 13: 115. 22998082 PMC3471047
  18. [18]Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013; 495: 384‐ 388. 23446346
  19. [19]Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013; 495: 333‐ 338. 23446348
  20. [21]Sekar S, Liang WS. Circular RNA expression and function in the brain. Noncoding RNA Res. 2019; 4: 23‐ 29. 30891534 PMC6404376
  21. [22]Post JM, Loch S, Lerner R, et al. Antiepileptogenic effect of subchronic palmitoylethanolamide treatment in a mouse model of acute epilepsy. Front Mol Neurosci. 2018; 11: 67. 29593494 PMC5861196
  22. [23]Srivastava S, Engels H, Schanze I, et al. Loss‐of‐function variants in HIVEP2 are a cause of intellectual disability. Eur J Hum Genet. 2016; 24: 556‐ 561. 26153216 PMC4929870
  23. [24]Steinfeld H, Cho MT, Retterer K, et al. Mutations in HIVEP2 are associated with developmental delay, intellectual disability, and dysmorphic features. Neurogenetics. 2016; 17: 159‐ 164. 27003583 PMC4907844
  24. [25]Wu LC. ZAS: C2H2 zinc finger proteins involved in growth and development. Gene Expr. 2002; 10: 137‐ 152. 12173742 PMC5977514
  25. [26]Fukuda S, Yamasaki Y, Iwaki T, et al. Characterization of the biological functions of a transcription factor, c‐myc intron binding protein 1 (MIBP1). J Biochem. 2002; 131: 349‐ 357. 11872163
  26. [27]Iwashita Y, Fukuchi N, Waki M, Hayashi K, Tahira T. Genome‐wide repression of NF‐kappaB target genes by transcription factor MIBP1 and its modulation by O‐linked beta‐N‐acetylglucosamine (O‐GlcNAc) transferase. J Biol Chem. 2012; 287: 9887‐ 9900. 22294689 PMC3323019
  27. [28]Goldsmith H, Wells A, Sa MJN, et al. Expanding the phenotype of intellectual disability caused by HIVEP2 variants. Am J Med Genet A. 2019; 179: 1872‐ 1877. 31207095
  28. [29]Lee M, Ban JJ, Yang S, Im W, Kim M. The exosome of adipose‐derived stem cells reduces beta‐amyloid pathology and apoptosis of neuronal cells derived from the transgenic mouse model of Alzheimer's disease. Brain Res. 2018; 1691: 87‐ 93. 29625119
  29. [30]Kalani A, Tyagi A, Tyagi N. Exosomes: mediators of neurodegeneration, neuroprotection and therapeutics. Mol Neurobiol. 2014; 49: 590‐ 600. 23999871 PMC3951279
  30. [31]Mehdizadeh A, Barzegar M, Negargar S, Yahyavi A, Raeisi S. The current and emerging therapeutic approaches in drug‐resistant epilepsy management. Acta Neurol Belg. 2019; 119: 155‐ 162. 30868468
  31. [32]Monory K, Massa F, Egertova M, et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron. 2006; 51: 455‐ 466. 16908411 PMC1769341
  32. [33]Zheng H, Tang R, Yao Y, et al. MiR‐219 protects against seizure in the kainic acid model of epilepsy. Mol Neurobiol. 2016; 53: 1‐ 7. 25394384
  33. [34]Geng W, Tang H, Luo S, et al. Exosomes from miRNA‐126‐modified ADSCs promotes functional recovery after stroke in rats by improving neurogenesis and suppressing microglia activation. Am J Transl Res. 2019; 11: 780‐ 792. 30899379 PMC6413259
  34. [35]Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004; 303: 83‐ 86. 14657504
  35. [36]Ryan DG, Oliveira‐Fernandes M, Lavker RM. MicroRNAs of the mammalian eye display distinct and overlapping tissue specificity. Mol Vis. 2006; 12: 1175‐ 1184. 17102797
  36. [37]Liguori M, Nuzziello N, Licciulli F, et al. Combined microRNA and mRNA expression analysis in pediatric multiple sclerosis: an integrated approach to uncover novel pathogenic mechanisms of the disease. Hum Mol Genet. 2018; 27: 66‐ 79. 29087462
  37. [38]Mao W, Huang X, Wang L, et al. Circular RNA hsa_circ_0068871 regulates FGFR3 expression and activates STAT3 by targeting miR‐181a‐5p to promote bladder cancer progression. J Exp Clin Cancer Res. 2019; 38: 169. 30999937 PMC6472097
  38. [39]Kawahara Y, Mieda‐Sato A. TDP‐43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc Natl Acad Sci USA. 2012; 109: 3347‐ 3352. 22323604 PMC3295278
  39. [40]Trabucchi M, Briata P, Garcia‐Mayoral M, et al. The RNA‐binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature. 2009; 459: 1010‐ 1014. 19458619 PMC2768332
  40. [41]Davis BN, Hilyard AC, Nguyen PH, Lagna G, Hata A. Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol Cell. 2010; 39: 373‐ 384. 20705240 PMC2921543
  41. [42]Han C, Liu Y, Wan G, et al. The RNA‐binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. Cell Rep. 2014; 8: 1447‐ 1460. 25176654 PMC4163106
  42. [43]Di Carlo V, Grossi E, Laneve P, et al. TDP‐43 regulates the microprocessor complex activity during in vitro neuronal differentiation. Mol Neurobiol. 2013; 48: 952‐ 963. 24113842
  43. [44]Dey BR, Spence SL, Nissley P, Furlanetto RW. Interaction of human suppressor of cytokine signaling (SOCS)‐2 with the insulin‐like growth factor‐I receptor. J Biol Chem. 1998; 273: 24095‐ 24101. 9727029
  44. [45]Singh A, Trevick S. The epidemiology of global epilepsy. Neurol Clin. 2016; 34: 837‐ 847. 27719996
  45. [46]Yuen AWC, Keezer MR, Sander JW. Epilepsy is a neurological and a systemic disorder. Epilepsy Behav. 2018; 78: 57‐ 61. 29175221
  46. [47]Golyala A, Kwan P. Drug development for refractory epilepsy: the past 25 years and beyond. Seizure. 2017; 44: 147‐ 156. 28017578
  47. [48]Cattani AA, Allene C, Seifert V, Rosenow F, Henshall DC, Freiman TM. Involvement of microRNAs in epileptogenesis. Epilepsia. 2016; 57: 1015‐ 1026. 27207608
  48. [49]Grabenstatter HL, Del Angel YC, Carlsen J, et al. The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy. Neurobiol Dis. 2014; 62: 73‐ 85. 24051278 PMC3908775
  49. [50]Okazaki T, Saito Y, Ueda R, et al. Epileptic phenotype of FGFR3‐related bilateral medial temporal lobe dysgenesis. Brain Dev. 2017; 39: 67‐ 71. 27485793
  50. [51]Romeo A, Lodi M, Viri M, et al. Does the co‐occurrence of FGFR3 gene mutation in hypochondroplasia, medial temporal lobe dysgenesis, and focal epilepsy suggest a syndrome? Pediatr Neurol. 2014; 50: 427‐ 430. 24630288
  51. [52]Song MY, Tian FF, Liu H, et al. Expression of SOCSs and TLRs in the hippocampus of pentylenetetrazole kindling model. Clin Lab. 2014; 60: 233‐ 240. 24660535
  52. [53]Baetz A, Frey M, Heeg K, Dalpke AH. Suppressor of cytokine signaling (SOCS) proteins indirectly regulate toll‐like receptor signaling in innate immune cells. J Biol Chem. 2004; 279: 54708‐ 54715. 15491991
  53. [54]French JA, Koepp M, Naegelin Y, et al. Clinical studies and anti‐inflammatory mechanisms of treatments. Epilepsia. 2017; 58(Suppl 3): 69‐ 82. 28675558 PMC5679081
  54. [55]Dey A, Kang X, Qiu J, Du Y, Jiang J. Anti‐inflammatory small molecules to treat seizures and epilepsy: from bench to bedside. Trends Pharmacol Sci. 2016; 37: 463‐ 484. 27062228 PMC5064857
  55. [56]Houser CR. Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res. 1990; 535: 195‐ 204. 1705855
  56. [57]Kralic JE, Ledergerber DA, Fritschy JM. Disruption of the neurogenic potential of the dentate gyrus in a mouse model of temporal lobe epilepsy with focal seizures. Eur J Neurosci. 2005; 22: 1916‐ 1927. 16262631
  57. [58]Heinrich C, Nitta N, Flubacher A, et al. Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus. J Neurosci. 2006; 26: 4701‐ 4713. 16641251 PMC6674063

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Authors
Xiaoying, G., Guo, M., Jie, L., Yanmei, Z., Ying, C., Shengjie, S., Haiyan, G., Feixiang, S., Sihua, Q., & Jiahang, S.
Affiliations
  • Department of Anesthesiology The Fourth Affiliated Hospital of Harbin Medical University Harbin China
  • Department of Neurosurgery The 2nd Affiliated Hospital of Harbin Medical University Harbin China
  • Department of Radiology The 2nd Affiliated Hospital of Harbin Medical University Harbin China
  • Department of Neurology The 2nd Affiliated Hospital of Harbin Medical University Harbin China
  • Department of Imageology The 2nd Affiliated Hospital of Harbin Medical University Harbin China
ORCID
Jiahang, Sun
Venue
Journal of Cellular and Molecular Medicine
Publisher
Wiley
Published
2020-10
Volume
24
Issue
22
Pages
12980-12993
ISSN
  • 1582-1838
  • 1582-4934
DOI
10.1111/jcmm.15894
PMC
PMC7701587
Cited by
50
References
1
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Natural Science Foundation of China (81871016, 2018M640306)
  • China Postdoctoral Science Foundation

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