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The role of inflammation in perinatal brain injury

Key Points

  • Perinatal brain injuries result from a spectrum of conditions, including neonatal encephalopathy, arterial ischaemic stroke, prematurity, and systemic infections

  • Depending on the timing and context, inflammation can prime the brain for injury or exert protective actions

  • Pattern recognition receptors, such as Toll-like receptors on innate immune cells (microglia, mast cells and macrophages), are important participants in the early phases of injury, and can increase CNS vulnerability (sensitization)

  • Inflammation during preterm labour and intensive care of premature infants affects the very immature brain during critical phases of brain development, with serious consequences for myelination and cortical development

  • Understanding the involvement of inflammation in perinatal brain injury can aid identification of new strategies for prevention and treatment that could reduce neurological and neuropsychiatric morbidities in maturing infants

Abstract

Inflammation is increasingly recognized as being a critical contributor to both normal development and injury outcome in the immature brain. The focus of this Review is to highlight important differences in innate and adaptive immunity in immature versus adult brain, which support the notion that the consequences of inflammation will be entirely different depending on context and stage of CNS development. Perinatal brain injury can result from neonatal encephalopathy and perinatal arterial ischaemic stroke, usually at term, but also in preterm infants. Inflammation occurs before, during and after brain injury at term, and modulates vulnerability to and development of brain injury. Preterm birth, on the other hand, is often a result of exposure to inflammation at a very early developmental phase, which affects the brain not only during fetal life, but also over a protracted period of postnatal life in a neonatal intensive care setting, influencing critical phases of myelination and cortical plasticity. Neuroinflammation during the perinatal period can increase the risk of neurological and neuropsychiatric disease throughout childhood and adulthood, and is, therefore, of concern to the broader group of physicians who care for these individuals.

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Figure 1: Inflammation in the developing brain.
Figure 2: Stages of inflammation in the immature brain after hypoxia–ischaemia and stroke.
Figure 3: Early innate response to hypoxia–ischaemia.
Figure 4: Mechanisms of TLR4 and TLR3 sensitization.
Figure 5: Effects of perinatal inflammation on brain development.

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Acknowledgements

All authors have received financial support from Leducq Foundation (DSRR_P34404). H.H. and P.G. have received a grant from Wellcome Trust programme (WT094823MA). NIH has funded D.M.F. (NS033997, 082330), Z.S.V. (RO1NS44025, NS76726) and S.J.V. (R21NS083425). The Swedish Medical Research Council has funded C.M. (VR2012-3500) and H.H. (VR2012-2992). ALF-LUA has funded C.M. (ALFGBG432291) and H.H. (ALFGBG426401). P.G. and C.M. have received the European Union grant FP7 (Neurobid, HEALTHF2-2009-241778). C.M. and H.H. have received funding from the Swedish Brain Foundation has funded (FO2013-095 for C.M., FO2013-0035 for H.H.), the Wilhelm & Martina Lundgren Foundation and the Frimurarna Barnhusdirektionen Foundation. Other funders include the Byggmästare Olle Engkvist Foundation (H.H.), ERA-Net, EU (VR 2014-7551; P.G. and H.H.), DHU PROTECT, INSERM, University Paris 7, (P.G.), the Fondation Graca de Monaco (P.G.), and the Fondation de Spoelberch (P.G.).

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Hagberg, H., Mallard, C., Ferriero, D. et al. The role of inflammation in perinatal brain injury. Nat Rev Neurol 11, 192–208 (2015). https://doi.org/10.1038/nrneurol.2015.13

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