Interleukin-1 Blockade Attenuates White Matter Inflammation and Oligodendrocyte Loss After Progressive Systematic Lipopolysaccharide Exposure in Near-Term Fetal Sheep

Abstract

\n BackgroundIncreased systemic and tissue levels of interleukin(IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration can attenuate neuroinflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS). MethodsChronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline (control, n=9), LPS infusions (0 h=300 ng, 24 h=600 ng, 48 h=1200 ng, n=8) or LPS plus 3 infusions of IL-1Ra (13 mg/kg infused over 4 h) started 1 h after each LPS infusion (n=9). Sheep were euthanized 4 days after starting infusions for histology.ResultsLPS infusions were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate (P<0.05 vs. control). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, apoptosis and microglial activation, and reduced astrocyte and total oligodendrocyte survival, but did not change myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and apoptosis, and improved total oligodendrocyte survival.ConclusionIL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss, but did not improve survival of astrocytes after LPS-induced inflammation in near-term fetal sheep. Further studies of long term brain maturation are now needed.