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308 TLR3 Activation Increases the Vulnerability of the Neonatal Brain to Hypoxia-Ischemia
  1. C Mallard,
  2. L Stridh,
  3. X Wang
  1. University of Gothenburg, Gothenburg, Sweden

Abstract

Background Activation of the innate immune system by bacterial products, via toll-like receptors (TLRs), has been shown to play a role in neonatal hypoxic-ischemic (HI) brain injury in mice. Less is known about how viral products affects neonatal HI. The aim of this study was to investigate the role of a synthetic mimic of double stranded RNA viral products (Poly I:C) in neonatal HI brain injury and whether these effects were dependent on TLR3 via its specific adaptor protein TRIF.

Method Neonatal wildtype (WT) and TRIF knock out (KO) mice were injected with Poly I:C and 14h later subjected to unilateral HI (10% O2, 36°C, 50 min). To evaluate brain damage, immunostaining for myelin basic protein (MBP) and microtubule associated protein-2 (MAP-2) were quantitatively analyzed 5 days after Poly I:C/HI. Cerebral mRNA expression was investigated for IFN-β, IL-6, IL-1β, TNF-α, MCP-1, IP-10 and Fas with RT-qPCR.

Results Poly I:C pre-treatment increased HI brain injury in WT mice, which was blocked in TRIF KO mice. Gene expression analyses showed a TRIF specific upregulation of IFN-β, IL-6, IL-1β, TNF-α, chemokines IP-10 and MCP-1 and the apoptotic mediator Fas.

In summary, the study shows that activation of TLR3 prior to HI increases neonatal brain injury. The sensitizing effect of Poly I:C was associated with release of a range of type I interferons, pro-inflammatory cytokines and chemokines. The results may indicate that viral infections in the neonate could have great impact on HI brain injury in the newborn.

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