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Perinatal inflammation, often caused by bacterial infection, is strongly linked with lifelong disability. We tested the hypothesis that IL-1 is a key mediator of inflammatory injury and evaluated whether systemic administration of IL-1 receptor antagonist (IL-1Ra) could attenuate cortical inflammation and improve neuronal development in late gestation fetal sheep exposed to TLR-4 mediated inflammation with lipopolysaccharide (LPS). Fetal sheep of both sexes, instrumented for continuous EEG, were randomised to: (1) saline infusion, (2) repeated intravenous LPS + vehicle infusions or (3) the same LPS regimen plus intravenous IL-1Ra infusions 1 h after each LPS dose. Four days later, brains were examined using RNA-seq, Golgi staining and immunohistochemistry. On EEG, LPS-exposure reduced relative beta power (high frequency EEG activity) compared to control, particularly in rapid eye movement sleep. In the somatosensory cortex, LPS-exposure decreased expression of genes involved in dendritogenesis and synaptogenesis, and increased genes involved in immune activation via LPS and IL-1 signalling. LPS-exposed fetuses had increased microglial activation and reduced neuronal arborisation. IL-1Ra treatment improved relative beta power, upregulated expression of genes involved in synaptogenesis, dendritogenesis and immune activation, reduced microglial activation, and improved neuronal arborisation. In summary, these findings indicate that IL-1 is a key driver of cortical neuronal injury associated with fetal inflammation and that IL-1Ra may improve neurodevelopmental outcomes following perinatal infection/inflammation.
Kelly et al. (Fri,) studied this question.