Lipopolysaccharide sensitizes neonatal hypoxic-ischemic brain injury in a MyD88-dependent manner.
Neurological deficits in children, including cerebral palsy, are associated with prior infection during the perinatal period. Experimentally, we have shown that pre-exposure to the Gram-negative component LPS potentiates hypoxic-ischemic (HI) brain injury in newborn animals. LPS effects are mediated by binding to TLR4, which requires recruitment of the MyD88 adaptor protein or Toll/IL-1R domain-containing adapter inducing IFN-beta for signal transduction. In this study, we investigated the role of MyD88 in neonatal brain injury. MyD88 knockout (MyD88 KO) and wild-type mice were subjected to left carotid artery ligation and 10% O(2) for 50 min on postnatal day 9. LPS or saline were administered i.p. at 14 h before HI. At 5 days after HI in wild-type mice, LPS in combination with HI caused a significant increase in gray and white matter tissue loss compared with the saline-HI group. By contrast, in the MyD88 KO mice there was no potentiation of brain injury with LPS-HI. MyD88 KO mice exhibited reduced NFkappaB activation and proinflammatory cytokine-chemokine expression in response to LPS. The number of microglia and caspase-3 activation was increased in the brain of MyD88 KO mice after LPS exposure. Collectively, these findings indicate that MyD88 plays an essential role in LPS-sensitized HI neonatal brain injury, which involves both inflammatory and caspase-dependent pathways.
Wang
Xiaoyang
X
Perinatal Center, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
Stridh
Linnea
L
Li
Wenli
W
Dean
Justin
J
Elmgren
Anders
A
Gan
Liming
L
Eriksson
Kristina
K
Hagberg
Henrik
H
Mallard
Carina
C
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D053148:Caspase 3 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D020925:Hypoxia-Ischemia, Brain / Q000276:immunology* / Q000473:pathology*; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016133:Polymerase Chain Reaction
D018925:Chemokines; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D053148:Caspase 3