The Cerebrospinal Fluid Inflammatory Response to Preterm Birth

Abstract

Background: Preterm birth is the leading risk factor for perinatal white matter injury, which can lead to motor and neuropsychiatric impairment across the life course. There is an unmet clinical need for therapeutics. White matter injury is associated with an altered inflammatory response in the brain, primarily led by microglia, and subsequent hypomyelination. However, microglia can release both damaging and trophic factors in response to injury, and a comprehensive assessment of these factors in the preterm central nervous system (CNS) has not been carried out.Method: A custom antibody array was used to assess relative levels of 50 inflammation- and myelination-associated proteins in the cerebrospinal fluid (CSF) of preterm infants in comparison to term controls.Results: Fifteen proteins differed between the groups: BDNF, BTC, C5a, FasL, Follistatin, IL-1β, IL-2, IL-4, IL-9, IL-17A, MIP-1α, MMP8, SPP1, TGFβ, and TNFβ (p < 0.05). To investigate the temporal regulation of these proteins after injury, we mined a gene expression dataset of microglia isolated from a mouse model of developmental white matter injury. Microglia in the experimental model showed dynamic temporal expression of genes encoding these proteins, with an initial and sustained pro-inflammatory response followed by a delayed anti-inflammatory response, and a continuous expression of genes predicted to inhibit healthy myelination.Conclusion: Preterm CSF shows a distinct neuroinflammatory profile compared to term controls, suggestive of a complex neural environment with concurrent damaging and reparative signals. We propose that limitation of pro-inflammatory responses, which occur early after perinatal insult, may prevent expression of myelination-suppressive genes and support healthy white matter development.

Brain volumetry in fetuses that deliver very preterm: An MRI pilot study

“…CSF plays a role in the removal of inflammatory cytokines and proteins secreted by neurons which may otherwise accumulate in brain tissue and have pathological effect on brain development ( Johanson et al, 2008 , Xie et al, 2013 ). CSF protein content has additionally been found to be altered in preterm born infants ( Boardman et al, 2018 ), undergoing lumbar puncture for suspected sepsis compared with term born infants with suspected sepsis and overall these changes represented increased prototypical pro-inflammatory responses. Although brain levels of these pro-inflammatory compounds could not be measured in their study, the levels of these significantly altered molecules were assessed in microglial cells isolated from a mouse model of inflammatory brain injury of the preterm born infant ( Van Steenwinckel et al, 2019 ).…”

Effect of Neuroprotective Magnesium Sulfate Treatment on Brain Transcription Response to Hypoxia Ischemia in Neonate Mice

“…In preterm subjects, increased Il-4 levels in the cerebrospinal fluid contributed to a cytokinic neuro-inflammatory profile [ 59 ]. In HI mice, Il-4 appeared as a pUR, suggesting an early regulatory function on the inflammation process.…”

White matter injury in the neonatal hypoxic‐ischemic brain and potential therapies targeting microglia

“…This condition is associated with M1 microglial expression of the pro‐inflammatory markers IL‐1β, iNOS, and TNF‐α (Fan et al., 2005). When IL‐1β was administered (by intraperitoneal injection) to P5 mice, microglia upregulated the expression of the pro‐inflammatory genes C5a (Hc), IL‐1β, IL‐2, and IL‐17a and downregulated the expression of IL‐4, effects that were predicted to inhibit OL differentiation and healthy myelination (Boardman et al., 2018). Based on the results of in vitro studies, activated microglia induce pre‐OL death in glial cultures following poly(I:C) stimulation, an effect that appears to be correlated with TNF‐α production (Steelman & Li, 2011).…”