Neonatal hydrocephalus leads to white matter neuroinflammation and injury in the corpus callosum of Ccdc39 hydrocephalic mice

View More View Less
  • 1 Department of Neurosurgery,
  • 2 Spinal Cord and Brain Injury Research Center, and
  • 4 Department of Physiology, University of Kentucky, Lexington, Kentucky; and
  • 3 Division of Pediatric Neurosurgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

OBJECTIVE

The authors sought to determine if hydrocephalus caused a proinflammatory state within white matter as is seen in many other forms of neonatal brain injury. Common causes of hydrocephalus (such as trauma, infection, and hemorrhage) are inflammatory insults themselves and therefore confound understanding of how hydrocephalus itself affects neuroinflammation. Recently, a novel animal model of hydrocephalus due to a genetic mutation in the Ccdc39 gene has been developed in mice. In this model, ciliary dysfunction leads to early-onset ventriculomegaly, astrogliosis, and reduced myelination. Because this model of hydrocephalus is not caused by an antecedent proinflammatory insult, it was utilized to study the effect of hydrocephalus on inflammation within the white matter of the corpus callosum.

METHODS

A Meso Scale Discovery assay was used to measure levels of proinflammatory cytokines in whole brain from animals with and without hydrocephalus. Immunohistochemistry was used to measure macrophage activation and NG2 expression within the white matter of the corpus callosum in animals with and without hydrocephalus.

RESULTS

In this model of hydrocephalus, levels of cytokines throughout the brain revealed a more robust increase in classic proinflammatory cytokines (interleukin [IL]–1β, CXCL1) than in immunomodulatory cytokines (IL-10). Increased numbers of macrophages were found within the corpus callosum. These macrophages were polarized toward a proinflammatory phenotype as assessed by higher levels of CD86, a marker of proinflammatory macrophages, compared to CD206, a marker for antiinflammatory macrophages. There was extensive structural damage to the corpus callosum of animals with hydrocephalus, and an increase in NG2-positive cells.

CONCLUSIONS

Hydrocephalus without an antecedent proinflammatory insult induces inflammation and tissue injury in white matter. Future studies with this model will be useful to better understand the effects of hydrocephalus on neuroinflammation and progenitor cell development. Antiinflammatory therapy for diseases that cause hydrocephalus may be a powerful strategy to reduce tissue damage.

ABBREVIATIONS AF = AlexaFluor; ICP = intracranial pressure; IFN = interferon; IL = interleukin; MSD = Meso Scale Discovery; OPC = oligodendrocyte progenitor cell; PBS = phosphate-buffered saline; PND10 = postnatal day 10; TNF = tumor necrosis factor; WT = wild-type.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Correspondence Brandon A. Miller: University of Kentucky, Lexington, KY. brandonmiller@uky.edu.

INCLUDE WHEN CITING Published online February 7, 2020; DOI: 10.3171/2019.12.PEDS19625.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • 1

    Abdelhamed Z, Vuong SM, Hill L, Shula C, Timms A, Beier D, : A mutation in Ccdc39 causes neonatal hydrocephalus with abnormal motile cilia development in mice. Development 145:145, 2018

    • Search Google Scholar
    • Export Citation
  • 2

    Ampofo E, Schmitt BM, Menger MD, Laschke MW: The regulatory mechanisms of NG2/CSPG4 expression. Cell Mol Biol Lett 22:4, 2017

  • 3

    Bachstetter AD, Rowe RK, Kaneko M, Goulding D, Lifshitz J, Van Eldik LJ: The p38α MAPK regulates microglial responsiveness to diffuse traumatic brain injury. J Neurosci 33:61436153, 2013

    • Search Google Scholar
    • Export Citation
  • 4

    Back SA: White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol 134:331349, 2017

  • 5

    Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS: Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med 3:7376, 1997

    • Search Google Scholar
    • Export Citation
  • 6

    Dendrou CA, Fugger L, Friese MA: Immunopathology of multiple sclerosis. Nat Rev Immunol 15:545558, 2015

  • 7

    Denker SP, Ji S, Dingman A, Lee SY, Derugin N, Wendland MF, : Macrophages are comprised of resident brain microglia not infiltrating peripheral monocytes acutely after neonatal stroke. J Neurochem 100:893904, 2007

    • Search Google Scholar
    • Export Citation
  • 8

    Emmert AS, Vuong SM, Shula C, Lindquist D, Yuan W, Hu YC, : Characterization of a novel rat model of X-linked hydrocephalus by CRISPR-mediated mutation in L1cam. J Neurosurg 132:945958, 2020

    • Search Google Scholar
    • Export Citation
  • 9

    Ernst LM, Gonzalez J, Ofori E, Elovitz M: Inflammation-induced preterm birth in a murine model is associated with increases in fetal macrophages and circulating erythroid precursors. Pediatr Dev Pathol 13:273281, 2010

    • Search Google Scholar
    • Export Citation
  • 10

    Garton TP, He Y, Garton HJ, Keep RF, Xi G, Strahle JM: Hemoglobin-induced neuronal degeneration in the hippocampus after neonatal intraventricular hemorrhage. Brain Res 1635:8694, 2016

    • Search Google Scholar
    • Export Citation
  • 11

    Gensel JC, Kopper TJ, Zhang B, Orr MB, Bailey WM: Predictive screening of M1 and M2 macrophages reveals the immunomodulatory effectiveness of post spinal cord injury azithromycin treatment. Sci Rep 7:40144, 2017

    • Search Google Scholar
    • Export Citation
  • 12

    Gensel JC, Zhang B: Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res 1619:111, 2015

  • 13

    Gram M, Sveinsdottir S, Ruscher K, Hansson SR, Cinthio M, Akerström B, : Hemoglobin induces inflammation after preterm intraventricular hemorrhage by methemoglobin formation. J Neuroinflammation 10:100, 2013

    • Search Google Scholar
    • Export Citation
  • 14

    Habiyaremye G, Morales DM, Morgan CD, McAllister JP, CreveCoeur TS, Han RH, : Chemokine and cytokine levels in the lumbar cerebrospinal fluid of preterm infants with post-hemorrhagic hydrocephalus. Fluids Barriers CNS 14:35, 2017

    • Search Google Scholar
    • Export Citation
  • 15

    Jensen FE: The role of glutamate receptor maturation in perinatal seizures and brain injury. Int J Dev Neurosci 20:339347, 2002

  • 16

    Jin X, Ishii H, Bai Z, Itokazu T, Yamashita T: Temporal changes in cell marker expression and cellular infiltration in a controlled cortical impact model in adult male C57BL/6 mice. PLoS One 7:e41892, 2012

    • Search Google Scholar
    • Export Citation
  • 17

    Kahle KT, Kulkarni AV, Limbrick DD Jr, Warf BC: Hydrocephalus in children. Lancet 387:788799, 2016

  • 18

    Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, : Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat Med 23:9971003, 2017

    • Search Google Scholar
    • Export Citation
  • 19

    Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG: Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29:1343513444, 2009

    • Search Google Scholar
    • Export Citation
  • 20

    Lan X, Han X, Li Q, Yang QW, Wang J: Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol 13:420433, 2017

    • Search Google Scholar
    • Export Citation
  • 21

    Lawrence T, Natoli G: Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 11:750761, 2011

    • Search Google Scholar
    • Export Citation
  • 22

    Mangano FT, McAllister JP II, Jones HC, Johnson MJ, Kriebel RM: The microglial response to progressive hydrocephalus in a model of inherited aqueductal stenosis. Neurol Res 20:697704, 1998

    • Search Google Scholar
    • Export Citation
  • 23

    Mattugini N, Merl-Pham J, Petrozziello E, Schindler L, Bernhagen J, Hauck SM, : Influence of white matter injury on gray matter reactive gliosis upon stab wound in the adult murine cerebral cortex. Glia 66:16441662, 2018

    • Search Google Scholar
    • Export Citation
  • 24

    McDonald JW, Levine JM, Qu Y: Multiple classes of the oligodendrocyte lineage are highly vulnerable to excitotoxicity. Neuroreport 9:27572762, 1998

    • Search Google Scholar
    • Export Citation
  • 25

    Miller BA, Crum JM, Tovar CA, Ferguson AR, Bresnahan JC, Beattie MS: Developmental stage of oligodendrocytes determines their response to activated microglia in vitro. J Neuroinflammation 4:28, 2007

    • Search Google Scholar
    • Export Citation
  • 26

    Morganti JM, Jopson TD, Liu S, Riparip LK, Guandique CK, Gupta N, : CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury. J Neurosci 35:748760, 2015

    • Search Google Scholar
    • Export Citation
  • 27

    Morganti JM, Riparip LK, Rosi S: Call off the dog(ma): M1/M2 polarization is concurrent following traumatic brain injury. PLoS One 11:e0148001, 2016

    • Search Google Scholar
    • Export Citation
  • 28

    Nishiyama A, Boshans L, Goncalves CM, Wegrzyn J, Patel KD: Lineage, fate, and fate potential of NG2-glia. Brain Res 1638 (Pt B):116128, 2016

    • Search Google Scholar
    • Export Citation
  • 29

    Ortega SB, Kong X, Venkataraman R, Savedra AM, Kernie SG, Stowe AM, : Perinatal chronic hypoxia induces cortical inflammation, hypomyelination, and peripheral myelin-specific T cell autoreactivity. J Leukoc Biol 99:2129, 2016

    • Search Google Scholar
    • Export Citation
  • 30

    Pang Y, Cai Z, Rhodes PG: Effect of tumor necrosis factor-α on developing optic nerve oligodendrocytes in culture. J Neurosci Res 80:226234, 2005

    • Search Google Scholar
    • Export Citation
  • 31

    Rezaie P, Dean A: Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system. Neuropathology 22:106132, 2002

    • Search Google Scholar
    • Export Citation
  • 32

    Rhodes KE, Raivich G, Fawcett JW: The injury response of oligodendrocyte precursor cells is induced by platelets, macrophages and inflammation-associated cytokines. Neuroscience 140:87100, 2006

    • Search Google Scholar
    • Export Citation
  • 33

    Rohlwink UK, Mauff K, Wilkinson KA, Enslin N, Wegoye E, Wilkinson RJ, : Biomarkers of cerebral injury and inflammation in pediatric tuberculous meningitis. Clin Infect Dis 65:12981307, 2017

    • Search Google Scholar
    • Export Citation
  • 34

    Schwartz M, Lazarov-Spiegler O, Rapalino O, Agranov I, Velan G, Hadani M: Potential repair of rat spinal cord injuries using stimulated homologous macrophages. Neurosurgery 44:10411046, 1999

    • Search Google Scholar
    • Export Citation
  • 35

    Stallcup WB: The NG2 proteoglycan in pericyte biology. Adv Exp Med Biol 1109:519, 2018

  • 36

    Stottmann RW, Moran JL, Turbe-Doan A, Driver E, Kelley M, Beier DR: Focusing forward genetics: a tripartite ENU screen for neurodevelopmental mutations in the mouse. Genetics 188:615624, 2011

    • Search Google Scholar
    • Export Citation
  • 37

    Strahle J, Garton HJ, Maher CO, Muraszko KM, Keep RF, Xi G: Mechanisms of hydrocephalus after neonatal and adult intraventricular hemorrhage. Transl Stroke Res 3 (Suppl 1):2538, 2012

    • Search Google Scholar
    • Export Citation
  • 38

    Sun F, Lin CL, McTigue D, Shan X, Tovar CA, Bresnahan JC, : Effects of axon degeneration on oligodendrocyte lineage cells: dorsal rhizotomy evokes a repair response while axon degeneration rostral to spinal contusion induces both repair and apoptosis. Glia 58:13041319, 2010

    • Search Google Scholar
    • Export Citation
  • 39

    Susarla BT, Villapol S, Yi JH, Geller HM, Symes AJ: Temporal patterns of cortical proliferation of glial cell populations after traumatic brain injury in mice. ASN Neuro 6:159170, 2014

    • Search Google Scholar
    • Export Citation
  • 40

    Ulfig N, Bohl J, Neudörfer F, Rezaie P: Brain macrophages and microglia in human fetal hydrocephalus. Brain Dev 26:307315, 2004

  • 41

    Wright Z, Larrew TW, Eskandari R: Pediatric hydrocephalus: current state of diagnosis and treatment. Pediatr Rev 37:478490, 2016

  • 42

    Yuan W, Deren KE, McAllister JP II, Holland SK, Lindquist DM, Cancelliere A, : Diffusion tensor imaging correlates with cytopathology in a rat model of neonatal hydrocephalus. Cerebrospinal Fluid Res 7:19, 2010

    • Search Google Scholar
    • Export Citation
  • 43

    Yuan W, McAllister JP II, Lindquist DM, Gill N, Holland SK, Henkel D, : Diffusion tensor imaging of white matter injury in a rat model of infantile hydrocephalus. Childs Nerv Syst 28:4754, 2012

    • Search Google Scholar
    • Export Citation
  • 44

    Zhang Z, Zhang Z, Lu H, Yang Q, Wu H, Wang J: Microglial polarization and inflammatory mediators after intracerebral hemorrhage. Mol Neurobiol 54:18741886, 2017

    • Search Google Scholar
    • Export Citation
  • 45

    Ziegelitz D, Arvidsson J, Hellström P, Tullberg M, Wikkelsø C, Starck G: Pre-and postoperative cerebral blood flow changes in patients with idiopathic normal pressure hydrocephalus measured by computed tomography (CT)-perfusion. J Cereb Blood Flow Metab 36:17551766, 2016

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 69 69 69
Full Text Views 16 16 16
PDF Downloads 26 26 26
EPUB Downloads 0 0 0