Cell-specific roles of GRK2 in onset and severity of hypoxic-ischemic brain damage in neonatal mice

Cora H. Nijboer, Cobi J. Heijnen, Hanneke L.D.M. Willemen, Floris Groenendaal, Gerald W. Dorn, Frank van Bel, Annemieke Kavelaars

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The ubiquitously expressed kinase GRK2 protects against cellular overstimulation by desensitizing G protein-coupled receptors and regulating intracellular signaling. Recently, we described that hypoxia-ischemia (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-GRK2f/+ mice) was sufficient to accelerate onset of HI damage, without affecting the severity of brain injury at 24h 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 3h 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-α than WT microglia via a p38-dependent pathway. In vivo, HI-induced cerebral p38 activation and TNF-α production were increased in GRK2+/- mice or in LysM-GRK2f/+ mice. Our findings indicate that low GRK2 in microglia/macrophages accelerates brain damage via a GRK2/p38/TNF-α-dependent pathway.Reduced GRK2 only in forebrain neurons (CamKIIα-GRK2f/+ 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-α production. The level of GRK2 in neurons is crucial for determining the ultimate severity of HI damage in the newborn brain.

Original languageEnglish
Pages (from-to)420-426
Number of pages7
JournalBrain, Behavior, and Immunity
Volume24
Issue number3
DOIs
StatePublished - Mar 2010

Keywords

  • G protein-coupled receptor kinase 2
  • Hypoxia-ischemia
  • Microglia
  • Minocycline
  • Neonatal
  • Neuron
  • P38
  • TNF-α

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