DOI QR코드

DOI QR Code

Reactive microglia and mitochondrial unfolded protein response following ventriculomegaly and behavior defects in kaolin-induced hydrocephalus

  • Zhu, Jiebo (Department of Medical Science, Chungnam National University School of Medicine) ;
  • Lee, Min Joung (Department of Medical Science, Chungnam National University School of Medicine) ;
  • Chang, Hee Jin (Department of Medical Science, Chungnam National University School of Medicine) ;
  • Ju, Xianshu (Department of Medical Science, Chungnam National University School of Medicine) ;
  • Cui, Jianchen (Department of Medical Science, Chungnam National University School of Medicine) ;
  • Lee, Yu Lim (Department of Medical Science, Chungnam National University School of Medicine) ;
  • Go, Dahyun (Department of Medical Science, Chungnam National University School of Medicine) ;
  • Chung, Woosuk (Department of Medical Science, Chungnam National University School of Medicine) ;
  • Oh, Eungseok (Department of Medical Science, Chungnam National University School of Medicine) ;
  • Heo, Jun Young (Department of Medical Science, Chungnam National University School of Medicine)
  • Received : 2021.09.04
  • Accepted : 2021.12.04
  • Published : 2022.04.30

Abstract

Ventriculomegaly induced by the abnormal accumulation of cerebrospinal fluid (CSF) leads to hydrocephalus, which is accompanied by neuroinflammation and mitochondrial oxidative stress. The mitochondrial stress activates mitochondrial unfolded protein response (UPRmt), which is essential for mitochondrial protein homeostasis. However, the association of inflammatory response and UPRmt in the pathogenesis of hydrocephalus is still unclear. To assess their relevance in the pathogenesis of hydrocephalus, we established a kaolin-induced hydrocephalus model in 8-week-old male C57BL/6J mice and evaluated it over time. We found that kaolin-injected mice showed prominent ventricular dilation, motor behavior defects at the 3-day, followed by the activation of microglia and UPRmt in the motor cortex at the 5-day. In addition, PARP-1/NF-κB signaling and apoptotic cell death appeared at the 5-day. Taken together, our findings demonstrate that activation of microglia and UPRmt occurs after hydrocephalic ventricular expansion and behavioral abnormalities which could be lead to apoptotic neuronal cell death, providing a new perspective on the pathogenic mechanism of hydrocephalus.

Keywords

Acknowledgement

This research was supported by the Ministry of Science, ICT (grant number NRF-2017R1A5A2015385, 2019M3E5D1A02068575, 2019R1F1A1059586).

References

  1. Kahle KT, Kulkarni AV, Limbrick DD Jr and Warf BC (2016) Hydrocephalus in children. Lancet 387, 788-799 https://doi.org/10.1016/S0140-6736(15)60694-8
  2. Levine DN (2008) Intracranial pressure and ventricular expansion in hydrocephalus: have we been asking the wrong question? J Neurol Sci 269, 1-11 https://doi.org/10.1016/j.jns.2007.12.022
  3. Ferris CF, Cai X, Qiao J et al (2019) Life without a brain: Neuroradiological and behavioral evidence of neuroplasticity necessary to sustain brain function in the face of severe hydrocephalus. Sci Rep 9, 16479 https://doi.org/10.1038/s41598-019-53042-3
  4. Chistyakov AV, Hafner H, Sinai A, Kaplan B and Zaaroor M (2012) Motor cortex disinhibition in normal-pressure hydrocephalus. J Neurosurg 116, 453-459 https://doi.org/10.3171/2011.9.JNS11678
  5. Lenfeldt N, Larsson A, Nyberg L et al (2008) Idiopathic normal pressure hydrocephalus: increased supplementary motor activity accounts for improvement after CSF drainage. Brain 131, 2904-2912 https://doi.org/10.1093/brain/awn232
  6. Olopade FE, Shokunbi MT and Siren AL (2012) The relationship between ventricular dilatation, neuropathological and neurobehavioural changes in hydrocephalic rats. Fluids Barriers CNS 9, 19 https://doi.org/10.1186/2045-8118-9-19
  7. Harris CA, Morales DM, Arshad R, McAllister JP 2nd and Limbrick DD Jr (2021) Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction. Fluids Barriers CNS 18, 4 https://doi.org/10.1186/s12987-021-00237-4
  8. Goulding DS, Vogel RC, Pandya CD et al (2020) Neonatal hydrocephalus leads to white matter neuroinflammation and injury in the corpus callosum of Ccdc39 hydrocephalic mice. J Neurosurg Pediatr 25, 476-483 https://doi.org/10.3171/2019.12.PEDS19625
  9. Czubowicz K, Glowacki M, Fersten E, Kozlowska E, Strosznajder RP and Czernicki Z (2017) Levels of selected pro- and anti-inflammatory cytokines in cerebrospinal fluid in patients with hydrocephalus. Folia Neuropathol 55, 301-307 https://doi.org/10.5114/fn.2017.72389
  10. Sosvorova L, Mohapl M, Vcelak J, Hill M, Vitku J and Hampl R (2015) The impact of selected cytokines in the follow-up of normal pressure hydrocephalus. Physiol Res 64, S283-S290
  11. Gaire BP and Choi JW (2021) Critical roles of lysophospholipid receptors in activation of neuroglia and their neuroinflammatory responses. Int J Mol Sci 22, 7864 https://doi.org/10.3390/ijms22157864
  12. Tarkowski E, Tullberg M, Fredman P and Wikkelso C (2003) Normal pressure hydrocephalus triggers intrathecal production of TNF-alpha. Neurobiol Aging 24, 707-714 https://doi.org/10.1016/S0197-4580(02)00187-2
  13. Wang Z, Zhang Y, Hu F, Ding J and Wang X (2020) Pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus. CNS Neurosci Ther 26, 1230-1240 https://doi.org/10.1111/cns.13526
  14. Chen Y, Zhou Z and Min W (2018) Mitochondria, oxidative stress and innate immunity. Front Physiol 9, 1487 https://doi.org/10.3389/fphys.2018.01487
  15. Melber A and Haynes CM (2018) UPR(mt) regulation and output: a stress response mediated by mitochondrial-nuclear communication. Cell Res 28, 281-295 https://doi.org/10.1038/cr.2018.16
  16. Sorrentino V, Menzies KJ and Auwerx J (2018) Repairing mitochondrial dysfunction in disease. Annu Rev Pharmacol Toxicol 58, 353-389 https://doi.org/10.1146/annurev-pharmtox-010716-104908
  17. Shpilka T and Haynes CM (2018) The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol 19, 109-120 https://doi.org/10.1038/nrm.2017.110
  18. Shen Y, Ding M, Xie Z et al (2019) Activation of mitochondrial unfolded protein response in SHSY5Y expressing APP cells and APP/PS1 mice. Front Cell Neurosci 13, 568 https://doi.org/10.3389/fncel.2019.00568
  19. Collins P (1979) Experimental obstructive hydrocephalus in the rat: a scanning electron microscopic study. Neuropathol Appl Neurobiol 5, 457-468 https://doi.org/10.1111/j.1365-2990.1979.tb00643.x
  20. Schob S, Weiss A, Dieckow J et al (2016) Correlations of ventricular enlargement with rheologically active surfactant proteins in cerebrospinal fluid. Front Aging Neurosci 8, 324
  21. Basati S, Desai B, Alaraj A, Charbel F and Linninger A (2012) Cerebrospinal fluid volume measurements in hydrocephalic rats. J Neurosurg Pediatr 10, 347-354 https://doi.org/10.3171/2012.6.PEDS11457
  22. Solana E, Poca MA, Sahuquillo J, Benejam B, Junque C and Dronavalli M (2010) Cognitive and motor improvement after retesting in normal-pressure hydrocephalus: a real change or merely a learning effect? J Neurosurg 112, 399-409 https://doi.org/10.3171/2009.4.JNS081664
  23. Osmon KJ, Vyas M, Woodley E, Thompson P and Walia JS (2018) Battery of behavioral tests assessing general locomotion, muscular strength, and coordination in mice. J Vis Exp 131, 55491
  24. Bloch O, Auguste KI, Manley GT and Verkman AS (2006) Accelerated progression of kaolin-induced hydrocephalus in aquaporin-4-deficient mice. J Cereb Blood Flow Metab 26, 1527-1537 https://doi.org/10.1038/sj.jcbfm.9600306
  25. Kim ST, Son HJ, Choi JH, Ji IJ and Hwang O (2010) Vertical grid test and modified horizontal grid test are sensitive methods for evaluating motor dysfunctions in the MPTP mouse model of Parkinson's disease. Brain Res 1306, 176-183 https://doi.org/10.1016/j.brainres.2009.09.103
  26. Khan OH, Enno TL and Del Bigio MR (2006) Brain damage in neonatal rats following kaolin induction of hydrocephalus. Exp Neurol 200, 311-320 https://doi.org/10.1016/j.expneurol.2006.02.113
  27. Spagnuolo C, Moccia S and Russo GL (2018) Anti-inflammatory effects of flavonoids in neurodegenerative disorders. Eur J Med Chem 153, 105-115 https://doi.org/10.1016/j.ejmech.2017.09.001
  28. Gisslen T, Ennis K, Bhandari V and Rao R (2015) Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex. Pediatr Res 78, 513-519 https://doi.org/10.1038/pr.2015.136
  29. Pan Z, Yang K, Wang H et al (2020) MFAP4 deficiency alleviates renal fibrosis through inhibition of NF-κB and TGF-β/Smad signaling pathways. FASEB J 34, 14250-14263 https://doi.org/10.1096/fj.202001026R
  30. Harland M, Torres S, Liu J and Wang X (2020) Neuronal mitochondria modulation of LPS-induced neuroinflammation. J Neurosci 40, 1756-1765 https://doi.org/10.1523/jneurosci.2324-19.2020
  31. Sosvorova L, Kanceva R, Vcelak J et al (2015) The comparison of selected cerebrospinal fluid and serum cytokine levels in patients with multiple sclerosis and normal pressure hydrocephalus. Neuro Endocrinol Lett 36, 564-571
  32. Park JC, Han SH and Mook-Jung I (2020) Peripheral inflammatory biomarkers in Alzheimer's disease: a brief review. BMB Rep 53, 10-19 https://doi.org/10.5483/BMBRep.2020.53.1.309
  33. Duru S, Oria M, Arevalo S et al (2019) Comparative study of intracisternal kaolin injection techniques to induce congenital hydrocephalus in fetal lamb. Childs Nerv Syst 35, 843-849 https://doi.org/10.1007/s00381-019-04096-1
  34. Silverberg GD, Miller MC, Pascale CL et al (2015) Kaolin-induced chronic hydrocephalus accelerates amyloid deposition and vascular disease in transgenic rats expressing high levels of human APP. Fluids Barriers CNS 12, 2 https://doi.org/10.1186/2045-8118-12-2
  35. Shim I, Ha Y, Chung JY, Lee HJ, Yang KH and Chang JW (2003) Association of learning and memory impairments with changes in the septohippocampal cholinergic system in rats with kaolin-induced hydrocephalus. Neurosurgery 53, 416-425; discussion 425 https://doi.org/10.1227/01.NEU.0000073989.07810.D8
  36. Xu H, Zhang SL, Tan GW et al (2012) Reactive gliosis and neuroinflammation in rats with communicating hydrocephalus. Neuroscience 218, 317-325 https://doi.org/10.1016/j.neuroscience.2012.05.004
  37. Olopade FE, Shokunbi MT, Azeez IA, Andrioli A, Scambi I and Bentivoglio M (2019) Neuroinflammatory response in chronic hydrocephalus in juvenile rats. Neuroscience 419, 14-22 https://doi.org/10.1016/j.neuroscience.2019.08.049
  38. Wu KY, Tang FL, Lee D et al (2020) Ependymal Vps35 promotes ependymal cell differentiation and survival, suppresses microglial activation, and prevents neonatal hydrocephalus. J Neurosci 40, 3862-3879 https://doi.org/10.1523/jneurosci.1520-19.2020
  39. Bras JP, Bravo J, Freitas J et al (2020) TNF-alpha-induced microglia activation requires miR-342: impact on NF-kB signaling and neurotoxicity. Cell Death Dis 11, 415 https://doi.org/10.1038/s41419-020-2626-6
  40. Takase H, Chou SH, Hamanaka G et al (2020) Soluble vascular endothelial-cadherin in CSF after subarachnoid hemorrhage. Neurology 94, e1281-e1293 https://doi.org/10.1212/wnl.0000000000008868
  41. Jimenez AJ, Rodriguez-Perez LM, Dominguez-Pinos MD et al (2014) Increased levels of tumour necrosis factor alpha (TNFα) but not transforming growth factor-beta 1 (TGFβ1) are associated with the severity of congenital hydrocephalus in the hyh mouse. Neuropathol Appl Neurobiol 40, 911-932 https://doi.org/10.1111/nan.12115
  42. Joshi AU, Minhas PS, Liddelow SA et al (2019) Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat Neurosci 22, 1635-1648 https://doi.org/10.1038/s41593-019-0486-0
  43. Hirsch EC and Hunot S (2009) Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol 8, 382-397 https://doi.org/10.1016/S1474-4422(09)70062-6
  44. Kwak JH and Lee K (2021) Forebrain glutamatergic neuron-specific Ctcf deletion induces reactive microgliosis and astrogliosis with neuronal loss in adult mouse hippocampus. BMB Rep 54, 317-322 https://doi.org/10.5483/BMBRep.2021.54.6.265
  45. Hassa PO and Hottiger MO (2002) The functional role of poly(ADP-ribose)polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell Mol Life Sci 59, 1534-1553 https://doi.org/10.1007/s00018-002-8527-2
  46. Malhotra U, Zaidi AH, Kosovec JE et al (2013) Prognostic value and targeted inhibition of survivin expression in esophageal adenocarcinoma and cancer-adjacent squamous epithelium. PLoS One 8, e78343 https://doi.org/10.1371/journal.pone.0078343
  47. Stoica BA, Loane DJ, Zhao Z et al (2014) PARP-1 inhibition attenuates neuronal loss, microglia activation and neurological deficits after traumatic brain injury. J Neurotrauma 31, 758-772 https://doi.org/10.1089/neu.2013.3194
  48. Niu LD, Xu W, Li JQ et al (2019) Genome-wide association study of cerebrospinal fluid neurofilament light levels in non-demented elders. Ann Transl Med 7, 657 https://doi.org/10.21037/atm.2019.10.66
  49. Fischer R and Maier O (2015) Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev 2015, 610813 https://doi.org/10.1155/2015/610813
  50. Lee Y, Park Y, Nam H, Lee JW and Yu SW (2020) Translocator protein (TSPO): the new story of the old protein in neuroinflammation. BMB Rep 53, 20-27 https://doi.org/10.5483/BMBRep.2020.53.1.273
  51. Delavallee L, Mathiah N, Cabon L et al (2020) Mitochondrial AIF loss causes metabolic reprogramming, caspase-independent cell death blockade, embryonic lethality, and perinatal hydrocephalus. Mol Metab 40, 101027 https://doi.org/10.1016/j.molmet.2020.101027
  52. D'Amico D, Sorrentino V and Auwerx J (2017) Cytosolic proteostasis networks of the mitochondrial stress response. Trends Biochem Sci 42, 712-725 https://doi.org/10.1016/j.tibs.2017.05.002
  53. Pharaoh G, Pulliam D, Hill S, Sataranatarajan K and Van Remmen H (2016) Ablation of the mitochondrial complex IV assembly protein Surf1 leads to increased expression of the UPR(MT) and increased resistance to oxidative stress in primary cultures of fibroblasts. Redox Biol 8, 430-438 https://doi.org/10.1016/j.redox.2016.05.001