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Toll-like receptor-3 activation increases the vulnerability of the neonatal brain to hypoxia-ischemia.

Journal article
Authors Linnea Stridh
Amin Mottahedin
Maria E Johansson
Raul Chavez Valdez
Frances Northington
Xiaoyang Wang
Carina Mallard
Published in The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume 33
Issue 29
Pages 12041-51
ISSN 1529-2401
Publication year 2013
Published at Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Physiology
Pages 12041-51
Language en
Keywords Adaptor Proteins, Vesicular Transport, genetics, metabolism, Animals, Brain, drug effects, immunology, metabolism, Hypoxia-Ischemia, Brain, immunology, metabolism, I-kappa B Proteins, metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Microglia, drug effects, immunology, metabolism, Phosphorylation, drug effects, Poly I-C, pharmacology, Proto-Oncogene Proteins c-akt, metabolism, Toll-Like Receptor 3, metabolism
Subject categories Basic Medicine, Experimental brain research


Susceptibility and progression of brain injury in the newborn is closely associated with an exacerbated innate immune response, but the underlying mechanisms are often unclear. Toll-like receptors (TLRs) are important innate immune sensors that may influence the vulnerability of the developing brain. In the current study, we provide novel data to show that activation of the viral innate immune receptor TLR-3 sensitizes the neonatal brain to subsequent hypoxic-ischemic (HI) damage. Poly inosinic:poly cytidylic acid (Poly I:C), a synthetic ligand for TLR-3, was administered to neonatal mice 14 h before cerebral HI. Activation of TLR-3 before HI increased infarct volume from 3.0 ± 0.5 to 15.4 ± 2.1 mm³ and augmented loss of myelin basic protein from 13.4 ± 6.0 to 70.6 ± 5.3%. The sensitizing effect of Poly I:C was specific for the TLR-3 pathway because mice deficient in the TLR-3 adaptor protein Toll/IL-1R domain-containing adaptor molecule-1 (TRIF) did not develop larger brain damage. The increased vulnerability was associated with a TRIF-dependent heightened inflammatory response, including proinflammatory cytokines, chemokines, and the apoptosis-associated mediator Fas, whereas there was a decrease in reparative M2-like CD11b⁺ microglia and phosphorylation of Akt. Because TLR-3 is activated via double-stranded RNA during most viral infections, the present study provides evidence that viral infections during pregnancy or in the neonate could have great impact on subsequent HI brain injury.

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