Interleukin-1 blockade attenuates white matter inflammation and oligodendrocyte loss after progressive systemic lipopolysaccharide exposure in near-term fetal sheep

Abstract

Background Increased 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 would attenuate brain inflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS). Methods Chronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline infusion (control, n = 9), repeated LPS infusions (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng, n = 8) or repeated LPS plus IL-1Ra infusions (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. Results LPS infusions increased circulating cytokines and 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 for all). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, numbers of caspase 3+ cells and microglia, reduced astrocyte and olig-2+ oligodendrocyte survival but did not change numbers of mature CC1+ oligodendrocytes, 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 caspase-3+ cells, and improved olig-2+ oligodendrocyte survival. Conclusion IL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss following LPS exposure in near-term fetal sheep. Further studies examining the long-term effects on brain maturation are now needed.

Increased Prostaglandin E2 in Brainstem Respiratory Centers Is Associated With Inhibition of Breathing Movements in Fetal Sheep Exposed to Progressive Systemic Inflammation

“…Moreover, we observed a reduction in the magnitude of LPS-induced hypoxemia, hypercapnia and acidosis, particularly after the third LPS infusion. This is consistent with previous studies from us and others that have shown tolerance to subsequent LPS doses ( Feng et al, 2009 ; Feng et al, 2010 ; Lear et al, 2014 ; Lear et al, 2015 ; Galinsky et al, 2020a ; Kelly et al, 2021 ). The immune tolerance is in part mediated by reprogramming of the innate immune system as shown by studies in human and sheep monocytes, whereby repeated LPS exposure is associated with decreased cytokine production and downregulation of the LPS receptor CD14 ( Mengozzi et al, 1993 ; Kramer et al, 2009 ).…”

“…In this study, we observed significant reductions in SaO 2 in LPS-exposed fetal sheep over the 3-day experimental period and we have previously reported increased production of pro-inflammatory cytokines, including IL-1β ( Kelly et al, 2021 ). Hypoxia and IL-1ß-induced inflammation rapidly increases microsomal prostaglandin E-synthase 1 (mPGES-1) expression within the rodent brainstem ( Hofstetter et al, 2007 ).…”

“…Fetuses received 300, 600, and 1200 ng infusions of LPS diluted in 2 mL of saline i.v. (infusion rate: 1 mL/min) on experimental days 1, 2, and 3, respectively, as previously described ( Kelly et al, 2021 ). This experimental model is relevant to the acute inflammatory exacerbations observed during perinatal infection/inflammation, which is associated with adverse neurodevelopmental outcomes ( Grether and Nelson, 1997 ; Yanowitz et al, 2002 ).…”

“…This experimental model is relevant to the acute inflammatory exacerbations observed during perinatal infection/inflammation, which is associated with adverse neurodevelopmental outcomes ( Grether and Nelson, 1997 ; Yanowitz et al, 2002 ). The incremental LPS infusions reduce tolerance to subsequent LPS infusions, when compared to using repeated LPS infusions of the same dose ( Rees et al, 2010 ; Kelly et al, 2021 ), thereby allowing us to more closely mimic the repeated inflammatory events observed in infants with an increased risk of developing neural injury ( Kuban et al, 2014 ). Controls received an equivalent volume of saline at the same infusion rate.…”

The Endocannabinoid System in Glial Cells and Their Profitable Interactions to Treat Epilepsy: Evidence from Animal Models

“…They can also release inflammatory mediators resulting in microglia activation and express cytokine receptors, promoting microglial recruitment to damage sites [234]. Remarkably, blockade of LPS-stimulated pro-inflammatory molecules decreases oligondendrocytic loss and reduces WM impairment [236].…”