| First Author | Nijboer CH | Year | 2010 |
| Journal | Brain Behav Immun | Volume | 24 |
| Issue | 3 | Pages | 420-6 |
| PubMed ID | 19932746 | Mgi Jnum | J:222368 |
| Mgi Id | MGI:5644409 | Doi | 10.1016/j.bbi.2009.11.009 |
| Citation | Nijboer CH, et al. (2010) Cell-specific roles of GRK2 in onset and severity of hypoxic-ischemic brain damage in neonatal mice. Brain Behav Immun 24(3):420-6 |
| abstractText | 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-GRK2(f/+) 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-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(f/+) 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 (CamKIIalpha-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. |
