title: Toll-like receptor-3 activation increases the vulnerability of the neonatal brain to hypoxia-ischemia.
abstract: 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.
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, S-40530 Gothenburg, Sweden.
authors.forename: Linnea
authors.initials: L
authors.lastname: Stridh
authors.forename: Amin
authors.initials: A
authors.lastname: Mottahedin
authors.forename: Maria E
authors.initials: ME
authors.lastname: Johansson
authors.forename: Raul Chavez
authors.initials: RC
authors.lastname: Valdez
authors.forename: Frances
authors.initials: F
authors.lastname: Northington
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wang
authors.forename: Carina
authors.initials: C
authors.lastname: Mallard
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000276:immunology / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D011070:Poly I-C / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D011070:Poly I-C; D051057:Proto-Oncogene Proteins c-akt; D051196:Toll-Like Receptor 3; C000606205:Nfkbia protein, mouse; C476286:Ticam1 protein, mouse