Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 24, Issue 3, Pages 420-426Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2009.11.009
Keywords
Hypoxia-ischemia; G protein-coupled receptor kinase 2; Microglia; p38; TNF-alpha; Minocycline; Neonatal; Neuron
Categories
Funding
- Wilhelmina Children's Hospital Fund
- European Commission [LSHM-CT-2006-036534,]
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The ubiquitously expressed kinase GRK2 protects against cellular overstimulation by desensitizing G protein-coupled receptors and regulating intracellular signaling. Recently, we described that hypoxiaischemia (Hi)-induced brain damage was accelerated and increased in GRK2(+/-) neonatal mice. Using Cre-Lox technology we now investigated the role of decreased GRK2 in only microglia/macrophages or forebrain neurons in development of HI brain injury. Low GRK2 in microglia/macrophages (LysM-GRK2(f/+) mice) was sufficient to accelerate onset of HI damage, without affecting the severity of brain injury at 24 h post-HI as compared to LysM-GRK2(+/+) littermates. Consistently, the ipsilateral hemisphere of GRK2(+/-) mice contained microglia with a more rounded phenotype compared to WT mice at 3 h post-HI. Inhibition of microglial/macrophage activity by minocycline treatment prevented the early onset of HI injury in GRK2(+/-) mice. In vitro, primary GRK2(+/-) microglia stimulated with LPS produced more TNF-alpha than WT microglia via a p38-dependent pathway. In vivo, HI-induced cerebral p38 activation and TNF-alpha production were increased in GRK2(+/-) mice or in LysM-GRK2(+/+) mice. Our findings indicate that low GRK2 in microglia/macrophages accelerates brain damage via a GRK2/p38/TNF-alpha-dependent pathway. Reduced GRK2 only in forebrain neurons (CamKII alpha-GRK2(f/+) mice) significantly increased severity of HI brain damage without affecting the onset of brain damage. In conclusion, our data indicate that low GRK2 in microglia/macrophages facilitates activation of these cells which may contribute to the earlier onset of cerebral HI injury associated with increased p38 phosphorylation and TNF-alpha production. The level of GRK2 in neurons is crucial for determining the ultimate severity of HI damage in the newborn brain. (C) 2009 Elsevier Inc. All rights reserved.
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