Chemokine and cytokine levels in the lumbar cerebrospinal fluid of preterm infants with post-hemorrhagic hydrocephalus

Abstract

BackgroundNeuroinflammation has been implicated in the pathophysiology of post-hemorrhagic hydrocephalus (PHH) of prematurity, but no comprehensive analysis of signaling molecules has been performed using human cerebrospinal fluid (CSF).MethodsLumbar CSF levels of key cytokines (IL-1α, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, TGF-β1, IFN-γ) and chemokines (XCL-1, CCL-2, CCL-3, CCL-19, CXCL-10, CXCL-11, CXCL-12) were measured using conventional and multiplexed Enzyme-linked Immunosorbent Assays and compared between preterm infants with PHH and those with no known neurological injury. The relationships between individual biomarker levels and specific CSF cell counts were examined.ResultsTotal protein (TP) CSF levels were elevated in the PHH subjects compared to controls. CSF levels of IL-1α, IL-4, IL-6, IL-12, TNF-α, CCL-3, CCL-19, and CXCL-10 were significantly increased in PHH whereas XCL-1 was significantly decreased in PHH. When normalizing by TP, IL-1α, IL-1β, IL-10, IL-12, CCL-3, and CCL-19 levels were significantly elevated compared to controls, while XCL-1 levels remained significantly decreased. Among those with significantly different levels in both absolute and normalized levels, only absolute CCL-19 levels showed a significant correlation with CSF nucleated cells, neutrophils, and lymphocytes. IL-1β and CXCL-10 also were correlated with total cell count, nucleated cells, red blood cells, and neutrophils.ConclusionsNeuroinflammation is likely to be an important process in the pathophysiology of PHH. To our knowledge, this is the first study to investigate CSF levels of chemokines in PHH as well as the only one to show XCL-1 selectively decreased in a diseased state. Additionally, CCL-19 was the only analyte studied that showed significant differences between groups and had significant correlation with cell count analysis. The selectivity of CCL-19 and XCL-1 should be further investigated. Future studies will further delineate the role of these cytokines and chemokines in PHH.

Mesenchymal Stem Cells for Severe Intraventricular Hemorrhage in Preterm Infants: Phase I Dose-Escalation Clinical Trial

“…Therefore, identifying additional biomarkers for the early identification of neuronal injury, in addition to cranial ultrasonography, is crucial for improving therapeutic outcomes 27. Various CSF biomarkers, including TGFß‐1 28, VEGF 29, BDNF 20, GDNF 30, and proinflammatory cytokines, such as IL‐1α 31, IL‐1ß 32, CCL‐3, and CCL‐19 31 have been used to diagnose brain injury and predict neurodevelopmental outcomes. In a previous study of brain‐specific proteins in the CSF, glial fibrillary acidic protein level was found to be substantially higher in infants with IVH and PHH than in normal infants.…”

Opportunities in posthemorrhagic hydrocephalus research: outcomes of the Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop

“…CSF levels of interleukin (IL)-1β, IL-6, IL-8, IL-18, transforming growth factor (TGF)-β1 and -β2, tumor necrosis factor (TNF)-α, and other cytokines and chemokines have all been implicated in PHH [ 194 – 200 ]. In a recent study by Habiyaremye et al [ 201 ], XCL-1 was decreased in the CSF of neonates with PHH. Levels of CCL-19, IL-1α, IL-1β, IL-12, and CCL-3 were elevated but only absolute CCL-19 levels correlated with levels of CSF nucleated cells, neutrophils, and lymphocytes [ 201 ].…”

Cerebrospinal Fluid Biomarkers of Neuroinflammation in Children with Hydrocephalus and Shunt Malfunction

“…This is in accordance with previous reporting that the highest risk of shunt failure is acute, which decreases over time and over number of revised shunts 43 , and the fact that hydrocephalus is more common in infants 6,9 . Data for healthy controls was retrieved from previous publications where similar multiplex ELISAs were performed using agematched patient CSF whenever possible [20][21][22]47 and added to the gures as a dotted line. All pediatric subjects underwent routine MRIs and/or CT to assist in the diagnosis of a shunt malfunction.…”

“…As many mechanisms underlying shunt failure elude researchers and clinicians, it is important to thoroughly investigate the CSF and environment surrounding the shunt catheters in addition examining to the e cacy of the catheters themselves 24,25 . To that end, this study rst looks at the protein concentration pro les of select pro-in ammatory and anti-in ammatory cytokines, as well as select matrix metalloproteinases (MMPs) in CSF at the time of shunt failure from patients with various hydrocephalus etiologies.…”