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Neonatal Hydrocephalus Leads to White Matter Neuroinflammation and Injury in the Corpus Callosum of Ccdc39 Hydrocephalic Mice

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Neonatal Hydrocephalus Leads to White Matter Neuroinflammation and Injury in the Corpus Callosum of Ccdc39 Hydrocephalic Mice LABORATORY INVESTIGATION J Neurosurg Pediatr 25:476–483, 2020 Neonatal hydrocephalus leads to white matter neuroinflammation and injury in the corpus callosum of Ccdc39 hydrocephalic mice Danielle S. Goulding, BS,1,2 R. Caleb Vogel, BS,1,2 Chirayu D. Pandya, PhD,1,2 Crystal Shula, BS,3 John C. Gensel, PhD,2,4 Francesco T. Mangano, DO,3 June Goto, PhD,3 and Brandon A. Miller, MD, PhD1,2 1Department of Neurosurgery, 2Spinal Cord and Brain Injury Research Center, and 4Department of Physiology, University of Kentucky, Lexington, Kentucky; and 3Division of Pediatric Neurosurgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 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 af- fects 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 proin- flammatory 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 neuroin- flammation and progenitor cell development. Antiinflammatory therapy for diseases that cause hydrocephalus may be a powerful strategy to reduce tissue damage. https://thejns.org/doi/abs/10.3171/2019.12.PEDS19625 KEYWORDS myelin; corpus callosum; microglia; neuroinflammation; hydrocephalus YDROCEPHALUS can be caused by many pathologi- hydrocephalus are lacking. There are also no guidelines cal events, including intracerebral hemorrhage, as to when hydrocephalus should be treated, especially trauma, and infection. Untreated hydrocephalus in cases in which children are born with dilated ventri- His often associated with progressive neurological injury, cles. A better mechanistic understanding of the causes of but good outcomes can be achieved with early diagnosis hydrocephalus and its consequences could provide more and CSF diversion surgery. Unfortunately, early prognos- targets for intervention and improve clinical outcomes tic biomarkers and efficacious medical therapies to treat by optimizing the timing of available treatments. 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. SUBMITTED October 23, 2019. ACCEPTED December 5, 2019. INCLUDE WHEN CITING Published online February 7, 2020; DOI: 10.3171/2019.12.PEDS19625. 476 J Neurosurg Pediatr Volume 25 • May 2020 ©AANS 2020, except where prohibited by US copyright law Unauthenticated | Downloaded 09/25/21 10:26 AM UTC Goulding et al. Recently, a model of neonatal hydrocephalus that is Hospital Medical Center, and studies were approved by due to a primary dysfunction of cilia within the brain has the Institutional Animal Care and Use Committee there. been developed.1,36 A mutation in the Ccdc39 gene that Wild-type (WT) littermate animals were used as controls. is selectively expressed in the choroid plexus and epen- All tissue used in this study was harvested from postnatal dymal cells of the embryonic brain results in early post- day 10 (PND10) pups that were maintained on a normal natal hydrocephalus, shortened lifespans, astrogliosis, and light/dark cycle and kept with their mother. The details of reduced myelination.1,36 Other forms of brain injury that this genetic model of hydrocephalus have been recently lead to hydrocephalus include trauma, infection, and in- published elsewhere.1 These animals experience short- tracerebral or intraventricular hemorrhage, all of which ened lifespans, and rapidly develop ventriculomegaly. At induce a robust neuroinflammatory reaction consisting PND10, these animals have reduced myelin production of activated microglia, macrophages, and astrocytes. The when compared to littermate controls.1 For all experi- neuroinflammation caused by these insults likely contrib- ments, animals were euthanized using CO2 and then de- utes to the development of hydrocephalus. However, the capitated. Brains were removed and processed for either effects the hydrocephalus itself has on neuroinflamma- immunohistochemical or biochemical endpoints. A total tion are not well understood. Therefore, this ciliopathy- of 14 mice were used in the study. induced model provides a unique opportunity to study the effects of hydrocephalus on inflammation, as opposed Immunohistochemistry to inflammation-mediated hydrocephalus. In addition, Tissue used for immunohistochemistry was immer- we previously observed a significant decrease in myelin sion-fixed in 4% paraformaldehyde for 18 hours at °4 C, production in this model, as evidenced by reduced my- before a series of phosphate-buffered saline (PBS) wash- elin basic protein levels indicating that hydrocephalus in- 1 es. Brains were then cryoprotected in a 15% sucrose/PBS duces myelination failure. Oligodendrocyte lineage cells solution for 18 hours, prior to final storage in 30% sucrose/ are exquisitely sensitive to inflammation present in other PBS solution. After bisecting the brain and embedding it neurological diseases such as multiple sclerosis and peri- 15,25,30 in optimal cutting temperature compound, 12-µm sagit- ventricular leukomalacia. In these forms of white tal sections were collected starting from the midline and matter disease, neuroinflammation is considered the pri- directly mounted onto charged slides and stored at −20°C mary mediator of oligodendrocyte progenitor cell (OPC) 4,6,31 until use. All staining was conducted with the use of Se- injury. In animal studies of CNS injury, OPCs increase quenza immunostaining racks (ThermoFisher Scientific). in number within injured white matter but do not reconsti- 29,38 Briefly, endogenous peroxidase activity was quenched tute lost myelin. White matter injury in kaolin-induced with 0.3% H O made in methanol (omitted for immuno- hydrocephalus models is also correlated with inflamma- 2 2 42,43 fluorescent staining) before blocking for nonspecific pro- tory burden. tein binding with either 10% goat or donkey serum and Several recent studies have established a link between 0.2% Triton X-100 in 1×PBS. All antibodies were dilut- hydrocephalus and neuroinflammation. Proinflammatory ed in a 1×PBS solution with 3% serum and 0.2% Triton cytokines are increased in the CSF of preterm infants with 14 X-100. For bright field microscopy analysis of NG2 (1:250, posthemorrhagic hydrocephalus, and animal studies of Millipore, ab5320), the biotinylated goat anti–rabbit sec- posthemorrhagic hydrocephalus are also associated with 13 ondary antibody (1:200, Vector, BA-1000) was amplified an inflammatory response. A prior study of rats with in- with an avidin-biotin system (ABC Elite kit, Vector), and herited aqueductal stenosis has shown an inflammatory 22 developed in 0.5 mg/ml 3,3′-diaminobenzidine tetrahy- response throughout the brain. CNS inflammation can drochloride solution (VWR). The slides were incubated also worsen the progression of hydrocephalus by induc- 18 with a nuclear counterstain (Methyl Green, Vector Labs) ing CSF overproduction. However, there is a growing and dehydrated before being coverslipped with Permount understanding that neuroinflammation is also reparative mounting media (Electron Microscopy Sciences). All im- in the CNS. Much of this work has focused on CNS mac- aging was performed with a Zeiss Axio Scan.Z1 at mag- rophages that can exhibit dual modalities in CNS injury. nification ×20. Macrophages react to local environmental cues to generate 21 complex, heterogeneous, and often opposing responses. Immunofluorescence Classically activated (“M1”) macrophages induce proin- flammatory responses often associated with tissue injury, Immunofluorescent analyses to evaluate macrophage whereas alternatively activated (“M2”) macrophages gen- heterogeneity11 were completed with images of colabeled erate antiinflammatory or proreparative responses.
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