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The activation of Microglia, Astroglia and Toll-like receptors in the immature human brain

Presented at the Neonatal Society 2011 Autumn Meeting.

Supramaniam V1, Vontell R2, Patkee P1, Wyatt-Ashmead J3, Hagberg H2, Rutherford M1

1 Perinatal Imaging Group, Imaging Sciences Department
2 Institute of Reproductive and Developmental Biology, Clinical Sciences Centre, MRC, Imperial College London
3 Wigglesworth Perinatal Pathology Services, St Mary’s/Hammersmith Hospital London, London, UK

Background: Preterm infants are at high risk of acquiring white matter injury, which is associated with poor outcomes. The periventricular (PV) WM in the immature brain is particularly susceptible to injury but the reasons are not fully understood. Glial cells are essential for brain development; microglia (MG) are involved in axonal guidance, myelination and synaptic pruning (1), while astroglia (AG) are critical in maintaining homeostasis in the immature brain and offer structural integrity to the vasculature in forming the blood-brain-barrier. However, there is a normal “overabundance” of MG in the developing PVWM, which may “prime” this area for injury (2). In contrast AG promote neuronal and oligodendrocyte (OL) survival during brain injury, and are vital in modulating the inflammatory response by MG during injury (3). The pattern recognition receptors, such as toll-like receptors (TLR) found on MG and AG cell membranes play a vital role in mediating immune response to injury by cytokine production and cell apoptosis. We hypothesise that there is an increased activation of MG and AG cells in the neonatal brain with known pathology and enhanced expression of TLRs.

Methods: PM neonatal cases (22-39wk GA) were recruited with parental consent and ethics approval. Images were acquired of formalin fixed PM brains at 3T with T1 and T2-weighted sequences. Iba1-, CD45-, CD68- (MG) and GFAP-, S100- (AG) immunopositive cell distribution TLR2, 3 and 4 expression in the immature brains.

Results: There was increased MG activation and reactive AG in the PVWM of the preterm cases with PVL but also with isolated GMH/IVH, or when there was evidence of ascending amniotic fluid infection without brain injury, compared to preterm cases with no overt brain injury on PM MRI and pathology examination. The PVL and infection cases showed the most prominent expression of all three TLRs. TLR3 expression was evident in MG and AG in the PVWM of GMH/IVH cases and TLR4 expression was seen in OLs in the PVL cases.

Conclusion: Activation of MG and AG cells through TLR receptors is associated with injury in the immature brain.

Corresponding author: veena.supramaniam@imperial.ac.uk

1. Paolicelli, R. C. et al. Synaptic pruning by microglia Is necessary for normal brain development. Science 333 1456-1458 (2001).
2. Billiards, S. S. et al. Development of microglia in the cerebral white matter of the human fetus and infant. Journal of Comparative Neurology 497, 199-208 (2006).
3. Min, K.-J., Yang, M.-s., Kim, S.-U., Jou, I. & Joe, E.-H. Astrocytes induce hemeoxygenase-1 expression in microglia: a feasible mechanism for preventing excessive brain inflammation. Journal of Neuroscience 26, 1880-7 (2006).

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