Neutralizing anti-interleukin-1β antibodies reduce ischemia-related interleukin-1β transport across the blood–brain barrier in fetal sheep

Abstract

Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1β (IL-1β) is a key mediator of inflammatory responses and elevated IL-1β levels in brain correlate with adverse neurodevelopmental outcomes after brain injury. Impaired blood-brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia-reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro-inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1β monoclonal antibody (mAb) reduce IL-1β transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo- or anti-IL-1β mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1β protein expressed from IL-1β pGEX-2T vectors in E. Coli BL-21 cells was produced, purified, and radiolabeled with 125I. BBB permeability was quantified using the blood-to-brain transfer constant (Ki) with 125I-radiolabeled-IL-1β. Increases in anti-IL-1β mAb were observed in the brain of the mAb-treated group (P<0.001). Blood-to-brain transport of 125I-IL-1β was lower (P<0.04) across brain regions in the anti-IL-1β mAb treated than placebo-treated ischemic fetuses. Plasma 125I-IL-1β counts were higher (P<0.001) in the anti-IL-1β mAb than placebo-treated ischemic fetuses. Systemic infusions of anti-IL-1β mAb reduce IL-1β transport across the BBB after ischemia in the ovine fetus. Our findings suggest that conditions associated with increases in systemic pro-inflammatory cytokines and neurodevelopmental impairment could benefit from an anti-cytokine therapeutic strategy.

Neuroimmune Axes of the Blood–Brain Barriers and Blood–Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions

“…In the short-term, it can result in seizures and an encephalopathy, and long-term it can result in cerebral palsy, impairments in hearing and vision, cognitive impairments, and problems with attention and irritability. In utero brain ischemia induces proinflammatory events, including increased increases in IL-1 β and IL-6 in the brains of both mothers and their fetuses ( Sadowska et al, 2012 ), opening of the fetal BBB, and increased cytokine transport into the fetal brain ( Chen et al, 2012 ; Sadowska et al, 2015 ; Patra et al, 2017 ). That these cytokine elevations are causal to brain damage is illustrated by the ability of blocking antibodies directed against IL-1 β and IL-6 to reduce cytokine transport across the BBB, reduce cytokine levels in brain, and attenuate or reverse BBB disruption ( Chen et al, 2015 ; Zhang et al, 2015 ; Patra et al, 2017 ).…”

Ischemic-Reperfusion Injury Increases Matrix Metalloproteinases and Tissue Metalloproteinase Inhibitors in Fetal Sheep Brain

“…We examined the cerebral cortex as it represents an important brain region, and because we had residual frozen frontal cerebral cortical samples from our previous studies [4,[29][30][31]. We have recently published a detailed schematic that we have used for our brain sample preparation in similar studies [32].…”

“…A coronal brain section of another half of the fetal brain was obtained at the level of the hypothalamus (mammillary bodies) for histopathological analysis [32]. The residual frozen brain from the frontal cortex was saved and used in prior publications [4,29,31,32] and for the current study in order to maximize information obtained from this complex large animal resource. Unfortunately, although we have previously measured BBB permeability and tight junction proteins in some of the fetal sheep reported in the current study, we did not have sufficient residual tissue remaining from the sham control animals.…”

“…The BBB transfer constant (K i ) used in the present study was from the same cohort of animals reported in our previous studies [4,29,31] and was measured with the BBB tracer α-[…”

Research progress of relationship between hyptoxic ischemic encephalopathy and interleukin in neonates

“…IL-1β is the earliest inflammatory cytokine that occurs after HIE hypoxic ischemic brain damage, and is also the key medium in the immunoregulation of neuroendocrine system. [7] Patra et al [8] have found that neonatal hypoxic and ischemic injury is an important cause of perinatal brain damage. Proinflammatory cytokines play an important role in the evolution of this brain injury.…”