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

Brain, Behavior, and Immunity
Cora NijboerAnnemieke Kavelaars

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-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/macro...Continue Reading

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