IL-1 modulation preserves biomolecular, structural and functional integrity of the somatosensory cortex after fetal inflammation

Perinatal inflammation, often caused by infection, is strongly linked with lifelong disability. Human and experimental studies identify interleukin-1 (IL-1), a pro-inflammatory cytokine, as a key mediator. We tested the hypothesis that systemic administration of IL-1 receptor antagonist (IL-1Ra) could attenuate cortical inflammation and improve neuronal development in late gestation fetal sheep exposed to lipopolysaccharide (LPS)-induced inflammation. Fetal sheep, 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 one hour after each LPS dose. Four-days later, brains were examined using RNAseq, Golgi staining and immunohistochemistry. On EEG, LPS-exposure reduced beta power compared to control, particularly in REM 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 EEG band power, normalised expression of genes involved in synaptogenesis, dendritogenesis and immune activation, reduced microglial activation, and restored neuronal arborisation. In summary, IL-1Ra reduced LPS-induced inflammation and improved biomolecular, structural and functional markers of neurodevelopment. Thus, IL-1Ra may improve neurodevelopmental outcomes following perinatal infection/inflammation.