Abstract
BackgroundIn very preterm infants, white matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury. Microglia and microvascular endothelial cells closely interact; therefore, a common signaling pathway may cause neuroinflammation and blood–brain barrier (BBB) damage after injury to the immature brain. CXC chemokine ligand 5 (CXCL5) is produced in inflammatory and endothelial cells by various organs in response to insults. CXCL5 levels markedly increased in the amniotic cavity in response to intrauterine infection and preterm birth in clinical studies. The objective of this study is to determine whether CXCL5 signaling is a shared pathway of neuroinflammation and BBB injury that contributes to white matter injury in the immature brain.MethodsPostpartum day 2 (P2) rat pups received lipopolysaccharide (LPS) followed by 90-min HI. Immunohistochemical analyses were performed to determine microglial activation, neutrophil infiltration, BBB damage, and myelin basic protein and glial fibrillary acidic protein expression. Immunofluorescence experiments were performed to determine the cellular distribution of CXCL5. Pharmacological tests were performed to inhibit or enhance CXCL5 activity.ResultsOn P2, predominant increases in microglial activation and BBB damage were observed 24 h after LPS-sensitized HI induction, and white matter injury (decreased myelination and increased astrogliosis) was observed on P12 compared with controls. Immunohistochemical analyses revealed increased CXCL5 expression in the white matter 6 and 24 h after insult. Immunofluorescence experiments revealed upregulated CXCL5 expression in the activated microglia and endothelial cells 24 h after insult. CXCL5 inhibition by SB225002, a selective nonpeptide inhibitor of CXCR2, significantly attenuated microglial activation and BBB damage, increased myelination, and reduced astrogliosis in the white matter after LPS-sensitized HI. In addition, CXCL5-sensitized HI or CXCL5 alone significantly induced BBB damage and white matter injury in association with different neuroinflammation mechanisms. CXCL5-sensitized HI-induced microglial activation and neutrophil infiltration, whereas CXCL5 alone predominately caused neutrophil infiltration.ConclusionsCXCL5 is a potential biomarker for white matter injury in preterm infants. Pharmacological blockade of CXCL5 signaling that attenuates dysregulated neuroinflammation can be used a therapeutic strategy against white matter injury in the immature brain.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0474-6) contains supplementary material, which is available to authorized users.
Highlights
In very preterm infants, white matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury
The CXC chemokine ligand 5 (CXCL5) expression was low in the white matter, and no significant difference was observed between the Postpartum day 2 (P2), P7, and P30 rats
The SB-3 group, but not the SB-1 group, had a significantly lower number of ED1(+) activated microglia (Fig. 5d) and significantly reduced blood–brain barrier (BBB) damage (Fig. 5e) in the white matter 24 h after insult compared with the vehicle group. These results suggest that the CXCL5–CXCR2 pathway plays an important role in microglial activation, BBB damage, and subsequent white matter injury after LPS-sensitized HI in the immature brain
Summary
White matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury. CXC chemokine ligand 5 (CXCL5) is produced in inflammatory and endothelial cells by various organs in response to insults. The objective of this study is to determine whether CXCL5 signaling is a shared pathway of neuroinflammation and BBB injury that contributes to white matter injury in the immature brain. Cytokines from monocytes and macrophages initiate inflammation by inducing chemokines released from inflammatory and endothelial cells [1, 2]. CXCL5 is expressed in many different cells, including monocytes, endothelial cells, and alveolar epithelial type II cells [3, 4]. It is expressed in various organs, such as the brain, during endotoxemia [5]. CXCL5 is produced by immune and vascular endothelial cells in response to proinflammatory cytokines through NF-kB activation [3, 6]
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