Journal
JOURNAL OF IMMUNOLOGY
Volume 183, Issue 11, Pages 7471-7477Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0900762
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Funding
- Swedish Medical Research Council [K2007-54x-14185-06-3, VR 2006-3396, VR 2009-54X-21119-01-4]
- European Commission [2006-036534/ncobrain]
- Ahlens stiftelsen
- Frimurare bamhusfonden
- Lundgrenska stiftelserna
- Swedish governmental [ALFGBG2863]
- National Natural Science Foundation of China [30973240]
- MRC [G0802853] Funding Source: UKRI
- Medical Research Council [G0802853] Funding Source: researchfish
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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 NF kappa B 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. The Journal of Immunology, 2009, 183: 7471-7477.
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