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MiRNA-210 induces microglial activation and regulates microglia-mediated neuroinflammation in neonatal hypoxic-ischemic encephalopathy

Cellular & Molecular Immunology volume 17, pages 976–991 (2020)Cite this article

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Abstract

Neuroinflammation is a major contributor to secondary neuronal injury that accounts for a significant proportion of final brain cell loss in neonatal hypoxic-ischemic encephalopathy (HIE). However, the immunological mechanisms that underlie HIE remain unclear. MicroRNA-210 (miR-210) is the master “hypoxamir” and plays a key role in hypoxic-ischemic tissue damage. Herein, we report in an animal model of neonatal rats that HIE significantly upregulated miR-210 expression in microglia in the neonatal brain and strongly induced activated microglia. Intracerebroventricular administration of miR-210 antagomir effectively suppressed microglia-mediated neuroinflammation and significantly reduced brain injury caused by HIE. We demonstrated that miR-210 induced microglial M1 activation partly by targeting SIRT1, thereby reducing the deacetylation of the NF-κB subunit p65 and increasing NF-κB signaling activity. Thus, our study identified miR-210 as a novel regulator of microglial activation in neonatal HIE, highlighting a potential therapeutic target in the treatment of infants with hypoxic-ischemic brain injury.

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References

  1. Li, B., Concepcion, K., Meng, X. & Zhang, L. Brain-immune interactions in perinatal hypoxic-ischemic brain injury. Prog. Neurobiol. 159, 50–68 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Davidson, J. O., Wassink, G., van den Heuij, L. G., Bennet, L. & Gunn, A. J. Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy—Where to from here? Front Neurol. 6, 198 (2015).

    PubMed  PubMed Central  Google Scholar 

  3. Wood, T. et al. Treatment temperature and insult severity influence the neuroprotective effects of therapeutic hypothermia. Sci. Rep. 6, 23430 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Deng, W. Neurobiology of injury to the developing brain. Nat. Rev. Neurol. 6, 328–336 (2010).

    PubMed  Google Scholar 

  5. Hagberg, H. et al. The role of inflammation in perinatal brain injury. Nat. Rev. Neurol. 11, 192–208 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Nelson, K. B., Dambrosia, J. M., Grether, J. K. & Phillips, T. M. Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann. Neurol. 44, 665–675 (1998).

    CAS  PubMed  Google Scholar 

  7. Bartha, A. I. et al. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatric Res. 56, 960–966 (2004).

    CAS  Google Scholar 

  8. Savman, K., Blennow, M., Gustafson, K., Tarkowski, E. & Hagberg, H. Cytokine response in cerebrospinal fluid after birth asphyxia. Pediatric Res. 43, 746–751 (1998).

    CAS  Google Scholar 

  9. Grether, J. K. & Nelson, K. B. Maternal infection and cerebral palsy in infants of normal birth weight. J. Am. Med. Assoc. 278, 207–211 (1997).

    CAS  Google Scholar 

  10. Kumar, H., Kawai, T. & Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34 (2011).

    CAS  PubMed  Google Scholar 

  11. Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. von Bernhardi, R., Eugenin-von Bernhardi, L. & Eugenin, J. Microglial cell dysregulation in brain aging and neurodegeneration. Front. Aging Neurosci. 7, 124 (2015).

    Google Scholar 

  13. Weinstein, J. R., Koerner, I. P. & Moller, T. Microglia in ischemic brain injury. Future Neurol. 5, 227–246 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Rocha-Ferreira, E. & Hristova, M. Antimicrobial peptides and complement in neonatal hypoxia-ischemia induced brain damage. Front. Immunol. 6, 56 (2015).

    PubMed  PubMed Central  Google Scholar 

  16. Kaur, C., Rathnasamy, G. & Ling, E. A. Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina. J. Neuroimmune Pharm. 8, 66–78 (2013).

    Google Scholar 

  17. Satoorian, T. et al. MicroRNA223 promotes pathogenic T-cell development and autoimmune inflammation in central nervous system in mice. Immunology 148, 326–338 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Li, B. et al. miR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunity. J. Clin. Investig. 127, 3702–3716 (2017).

    PubMed  Google Scholar 

  19. Tsitsiou, E. & Lindsay, M. A. microRNAs and the immune response. Curr. Opin. Pharm. 9, 514–520 (2009).

    CAS  Google Scholar 

  20. Baltimore, D., Boldin, M. P., O’Connell, R. M., Rao, D. S. & Taganov, K. D. MicroRNAs: new regulators of immune cell development and function. Nat. Immunol. 9, 839–845 (2008).

    CAS  PubMed  Google Scholar 

  21. Huang, X., Le, Q. T. & Giaccia, A. J. MiR-210–micromanager of the hypoxia pathway. Trends Mol. Med. 16, 230–237 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kulshreshtha, R. et al. A microRNA signature of hypoxia. Mol. Cell Biol. 27, 1859–1867 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Mok, Y. et al. MiR-210 is induced by Oct-2, regulates B cells, and inhibits autoantibody production. J. Immunol. 191, 3037–3048 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang, H. et al. Negative regulation of Hif1a expression and TH17 differentiation by the hypoxia-regulated microRNA miR-210. Nat. Immunol. 15, 393–401 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang, D., Cao, X., Li, J. & Zhao, G. MiR-210 inhibits NF-kappaB signaling pathway by targeting DR6 in osteoarthritis. Sci. Rep. 5, 12775 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, L. et al. Inhibition of miRNA-210 reverses nicotine-induced brain hypoxic-ischemic injury in neonatal rats. Int. J. Biol. Sci. 13, 76–84 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ma, Q. et al. Inhibition of microRNA-210 provides neuroprotection in hypoxic-ischemic brain injury in neonatal rats. Neurobiol. Dis. 89, 202–212 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Endo, K. et al. MicroRNA 210 as a biomarker for congestive heart failure. Biol. Pharm. Bull. 36, 48–54 (2013).

    CAS  PubMed  Google Scholar 

  29. Zeng, L. et al. MicroRNA-210 as a novel blood biomarker in acute cerebral ischemia. Front Biosci. 3, 1265–1272 (2011).

    Google Scholar 

  30. Vannucci, R. C. & Vannucci, S. J. Perinatal hypoxic-ischemic brain damage: evolution of an animal model. Dev. Neurosci. 27, 81–86 (2005).

    CAS  PubMed  Google Scholar 

  31. Rathnasamy, G., Ling, E. A. & Kaur, C. Iron and iron regulatory proteins in amoeboid microglial cells are linked to oligodendrocyte death in hypoxic neonatal rat periventricular white matter through production of proinflammatory cytokines and reactive oxygen/nitrogen species. J. Neurosci. 31, 17982–17995 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kinney, H. C. Human myelination and perinatal white matter disorders. J. Neurol. Sci. 228, 190–192 (2005).

    CAS  PubMed  Google Scholar 

  33. Liu, F. & McCullough, L. D. Inflammatory responses in hypoxic ischemic encephalopathy. Acta Pharm. Sin. 34, 1121–1130 (2013).

    Google Scholar 

  34. Yeung, F. et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369–2380 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu, T. F. & McCall, C. E. Deacetylation by SIRT1 Reprograms Inflammation and Cancer. Genes Cancer 4, 135–147 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Xiong, L. et al. DNA demethylation regulates the expression of miR-210 in neural progenitor cells subjected to hypoxia. FEBS J. 279, 4318–4326 (2012).

    CAS  PubMed  Google Scholar 

  37. Fasanaro, P. et al. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J. Biol. Chem. 283, 15878–15883 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Biswas, S. et al. Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds. Proc. Natl Acad. Sci. USA 107, 6976–6981 (2010).

    CAS  PubMed  Google Scholar 

  39. Taylor, C. T. & Colgan, S. P. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat. Rev. Immunol. 17, 774–785 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Zaccagnini, G. et al. Overexpression of miR-210 and its significance in ischemic tissue damage. Sci. Rep. 7, 9563 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Qi, J. et al. microRNA-210 negatively regulates LPS-induced production of proinflammatory cytokines by targeting NF-kappaB1 in murine macrophages. FEBS Lett. 586, 1201–1207 (2012).

    CAS  PubMed  Google Scholar 

  42. Bakirtzi, K. et al. Neurotensin promotes the development of colitis and intestinal angiogenesis via Hif-1alpha-miR-210 Signaling. J. Immunol. 196, 4311–4321 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wu, R. et al. MicroRNA-210 overexpression promotes psoriasis-like inflammation by inducing Th1 and Th17 cell differentiation. J. Clin. Investig. 128, 2551–2568 (2018).

    PubMed  Google Scholar 

  44. Zhao, M. et al. Up-regulation of microRNA-210 induces immune dysfunction via targeting FOXP3 in CD4(+) T cells of psoriasis vulgaris. Clin. Immunol. 150, 22–30 (2014).

    CAS  PubMed  Google Scholar 

  45. Kopriva, S. E., Chiasson, V. L., Mitchell, B. M. & Chatterjee, P. TLR3-induced placental miR-210 down-regulates the STAT6/interleukin-4 pathway. PLoS ONE 8, e67760 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Huang, L., Ma, Q., Li, Y., Li, B. & Zhang, L. Inhibition of microRNA-210 suppresses pro-inflammatory response and reduces acute brain injury of ischemic stroke in mice. Exp. Neurol. 300, 41–50 (2018).

    CAS  PubMed  Google Scholar 

  47. Ponomarev, E. D., Veremeyko, T., Barteneva, N., Krichevsky, A. M. & Weiner, H. L. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-alpha-PU.1 pathway. Nat. Med. 17, 64–70 (2011).

    CAS  PubMed  Google Scholar 

  48. Zhao, H. et al. MiRNA-424 protects against permanent focal cerebral ischemia injury in mice involving suppressing microglia activation. Stroke 44, 1706–1713 (2013).

    CAS  PubMed  Google Scholar 

  49. Ni, J. et al. MicroRNA let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation. Brain Behav. Immun. 49, 75–85 (2015).

    CAS  PubMed  Google Scholar 

  50. Parisi, C. et al. MicroRNA-125b regulates microglia activation and motor neuron death in ALS. Cell Death Differ. 23, 531–541 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang, X. et al. miRNA-3473b contributes to neuroinflammation following cerebral ischemia. Cell Death Dis. 9, 11 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).

    CAS  PubMed  Google Scholar 

  53. Varol, D. et al. Dicer deficiency differentially impacts microglia of the developing and adult brain. Immunity 46, 1030–1044 e1038 (2017).

    CAS  PubMed  Google Scholar 

  54. Monje, M. L., Toda, H. & Palmer, T. D. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760–1765 (2003).

    CAS  PubMed  Google Scholar 

  55. Sun, J. J. et al. MiRNA-210 induces the apoptosis of neuronal cells of rats with cerebral ischemia through activating HIF-1alpha-VEGF pathway. Eur. Rev. Med. Pharm. Sci. 23, 2548–2554 (2019).

    Google Scholar 

  56. Ma Q., Dasgupta C., Li Y., & Huang L., Zhang L. MicroRNA-210 downregulates ISCU and induces mitochondrial dysfunction and neuronal death in neonatal hypoxic-ischemic brain injury. Mol. Neurobiol. 2019. https://doi.org/10.1007/s12035-019-1491-8

  57. Qiu, J. et al. Neuroprotective effects of microRNA-210 on hypoxic-ischemic encephalopathy. Biomed. Res. Int. 2013, 350419 (2013).

    PubMed  PubMed Central  Google Scholar 

  58. Zeng, L. et al. MicroRNA-210 overexpression induces angiogenesis and neurogenesis in the normal adult mouse brain. Gene Ther. 21, 37–43 (2014).

    CAS  PubMed  Google Scholar 

  59. Meng Z. Y., et al. MicroRNA-210 promotes accumulation of neural precursor cells around ischemic foci after cerebral ischemia by regulating the SOCS1-STAT3-VEGF-C pathway. J. Am. Heart Assoc. 7, e005052 (2018)

  60. Voloboueva, L. A., Sun, X., Xu, L., Ouyang, Y. B. & Giffard, R. G. Distinct effects of miR-210 reduction on neurogenesis: increased neuronal survival of inflammation but reduced proliferation associated with mitochondrial enhancement. J. Neurosci. 37, 3072–3084 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Chio, C. C. et al. MicroRNA-210 targets antiapoptotic Bcl-2 expression and mediates hypoxia-induced apoptosis of neuroblastoma cells. Arch. Toxicol. 87, 459–468 (2013).

    CAS  PubMed  Google Scholar 

  62. Wang, F. et al. miR-210 suppresses BNIP3 to protect against the apoptosis of neural progenitor cells. Stem Cell Res. 11, 657–667 (2013).

    CAS  PubMed  Google Scholar 

  63. Luan, Y., Zhang, X., Zhang, Y. & Dong, Y. MicroRNA-210 Protects PC-12 Cells Against Hypoxia-Induced Injury by Targeting BNIP3. Front. Cell. Neurosci. 11, 285 (2017).

    PubMed  PubMed Central  Google Scholar 

  64. Hu, Y. W., Jiang, J. J., Yan, G., Wang, R. Y. & Tu, G. J. MicroRNA-210 promotes sensory axon regeneration of adult mice in vivo and in vitro. Neurosci. Lett. 622, 61–66 (2016).

    CAS  PubMed  Google Scholar 

  65. ElAli, A. & Rivest, S. Microglia ontology and signaling. Front. Cell Dev. Biol. 4, 72 (2016).

    PubMed  PubMed Central  Google Scholar 

  66. Hyakkoku, K. et al. Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia. Neuroscience 171, 258–267 (2010).

    CAS  PubMed  Google Scholar 

  67. Ginhoux, F., Lim, S., Hoeffel, G., Low, D. & Huber, T. Origin and differentiation of microglia. Front. Cell. Neurosci. 7, 45 (2013).

    PubMed  PubMed Central  Google Scholar 

  68. Wu, Y. et al. Overexpression of Sirtuin 6 suppresses cellular senescence and NF-kappaB mediated inflammatory responses in osteoarthritis development. Sci. Rep. 5, 17602 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    CAS  Google Scholar 

  70. Chen, Z., Li, Y., Zhang, H., Huang, P. & Luthra, R. Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression. Oncogene 29, 4362–4368 (2010).

    CAS  PubMed  Google Scholar 

  71. Wang, Y., Ni, H., Zhang, W., Wang, X. & Zhang, H. Downregulation of miR-210 protected bupivacaine-induced neurotoxicity in dorsal root ganglion. Exp. Brain Res. 234, 1057–1065 (2016).

    CAS  PubMed  Google Scholar 

  72. Kelly, T. J., Souza, A. L., Clish, C. B. & Puigserver, P. A hypoxia-induced positive feedback loop promotes hypoxia-inducible factor 1alpha stability through miR-210 suppression of glycerol-3-phosphate dehydrogenase 1-like. Mol. Cell. Biol. 31, 2696–2706 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Mohammad, M. G. et al. Immune cell trafficking from the brain maintains CNS immune tolerance. J. Clin. Investig. 124, 1228–1241 (2014).

    CAS  PubMed  Google Scholar 

  74. Tamashiro T. T., Dalgard C. L., & Byrnes K. R. Primary microglia isolation from mixed glial cell cultures of neonatal rat brain tissue. J. Vis. Exp. 66, e3814 (2012).

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Acknowledgements

We thank the animal facility of Loma Linda University (LLU) for providing animal support; the LLU Flow Cytometry Education and Training Core Facility for providing flow cytometry support; and the LLU animal imaging facility for providing MRI support. This work was supported by the National Institutes of Health grants HL118861 (LZ) and NS103017 (LZ).

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  1. Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA

    Bo Li, Chiranjib Dasgupta, Lei Huang, Xianmei Meng & Lubo Zhang

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  1. Bo Li
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B.L. designed and conducted the experiments, analyzed the data, and wrote the manuscript. C.D. and L.H. conducted experiments and analyzed data. X.M. conducted experiments. L.Z. conceived and designed the studies, interpreted the data, and wrote the manuscript.

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Correspondence to Bo Li or Lubo Zhang.

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Li, B., Dasgupta, C., Huang, L. et al. MiRNA-210 induces microglial activation and regulates microglia-mediated neuroinflammation in neonatal hypoxic-ischemic encephalopathy. Cell Mol Immunol 17, 976–991 (2020). https://doi.org/10.1038/s41423-019-0257-6

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