Tumor necrosis factor inhibition attenuates white matter gliosis after systemic inflammation in preterm fetal sheep

Abstract

Background: Increased circulating levels of tumor necrosis factor (TNF) are associated with greater risk of impaired neurodevelopment after preterm birth. In this study, we tested the hypothesis that systemic TNF inhibition, using the soluble TNF receptor Etanercept, would attenuate neuroinflammation in preterm fetal sheep exposed to lipopolysaccharide (LPS). Methods: Chronically instrumented preterm fetal sheep at 0.7 of gestation were randomly assigned to receive saline (control; n = 7), LPS infusion (100 ng/kg i.v. over 24 h then 250 ng/kg/24 h for 96 h plus 1 μg LPS boluses at 48, 72, and 96 h, to induce inflammation; n = 8) or LPS plus two i.v. infusions of Etanercept (2 doses, 5 mg/kg infused over 30 min, 48 h apart) started immediately before LPS-exposure (n = 8). Sheep were killed 10 days after starting infusions, for histology. Results: LPS boluses were associated with increased circulating TNF, interleukin (IL)-6 and IL-10, electroencephalogram (EEG) suppression, hypotension, tachycardia, and increased carotid artery perfusion (P < 0.05 vs. control). In the periventricular and intragyral white matter, LPS exposure increased gliosis, TNFpositive cells, total oligodendrocytes, and cell proliferation (P < 0.05 vs control), but did not affect myelin expression or numbers of neurons in the cortex and subcortical regions. Etanercept delayed the rise in circulating IL-6, prolonged the increase in IL-10 (P < 0.05 vs. LPS), and attenuated EEG suppression, hypotension, and tachycardia after LPS boluses. Histologically, Etanercept normalized LPS-induced gliosis, and increase in TNF-positive cells, proliferation, and total oligodendrocytes. Conclusion: TNF inhibition markedly attenuated white matter gliosis but did not affect mature oligodendrocytes after prolonged systemic inflammation in preterm fetal sheep. Further studies of long-term brain maturation are now needed.

Magnetic Resonance Imaging Correlates of White Matter Gliosis and Injury in Preterm Fetal Sheep Exposed to Progressive Systemic Inflammation

“…Furthermore, in LPS-exposed fetuses, we observed an increase in astrocyte coherence (anisotropy) compared to that in the vehicle controls, and a positive linear relationship was observed between astrocyte coherence and FA. While MRI and histological analyses were performed on matched sections from contralateral hemispheres, in previous studies from our laboratory, we have consistently found similar changes in both hemispheres after systemic LPS exposure [17,32]. This is further supported by our observation of reduced anisotropy on both histological and MRI assessment in the current study.…”

Immune Factor, TNFα, Disrupts Human Brain Organoid Development Similar to Schizophrenia—Schizophrenia Increases Developmental Vulnerability to TNFα

“…The scar-like regions contained displaced highly concentrated pan-Neu stained neurons ( Figure 1C2 ) as well as GFAP stained glia ( Supplementary Figure S1B ). The latter may reflect a gliosis-like response to TNF observed in vivo (Livne-Bar et al, 2016 ; Galinsky et al, 2020 ).…”

The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications

“…Briefly, the evidence in support of this concept indicates that 1) proven intra-amniotic infection is present in at least 25% of all preterm deliveries [209][210][211][212][213][214][215] and in 61% of patients with clinical chorioamnionitis at term [216]; 2) a fetal inflammatory response (diagnosed by the presence of funisitis, elevated concentrations of IL-6 or C-reactive protein in umbilical cord blood) is present in a large fraction of patients with intra-amniotic infection [9,217,218]; 3) there is a strong association between intra-amniotic infection/inflammation and the subsequent development of white matter lesions of the neonatal brain [219][220][221][222][223][224][225][226][227][228][229][230][231][232][233][234][235][236][237]; 4) a fetal inflammatory response (diagnosed by funisitis) increases the risk of both periventricular leukomalacia and cerebral palsy [9,20,[192][193][194][195]; 5) intrauterine infection with bacteria or intra-amniotic administration of LPS can induce a fetal systemic inflammatory response, neuroinflammation, and lesions resembling periventricular leukomalacia with gliosis and neuronal injury [193,[223][224][225]…”