MerTK and the Role of Phagoptosis in Neonatal Hypoxia-Ischemia

Brain damage caused by hypoxia-ischemia is a serious complication for a newborn with possible life-long sequelae. To develop targeted neuroprotective strategies, it is essential to understand the mechanisms of injury, particularly the role of microglial phagocytosis, which may contribute to neuronal loss after hypoxia-ischemia. The aim was to evaluate neuronal cell death by phagocytosis in neonatal hypoxia-ischemia by investigating key signaling molecules and the effect of gene deletion of the phagocytic receptor Myeloid-epithelial-reproductive tyrosine kinase (MerTK) in a neonatal mouse model. MerTK, growth arrest-specific 6, and genes related to phagoptosis were regulated in the brain 6-72 h after hypoxic ischemia. Brain injury was reduced in MerTK knock-out vs. wild-type mice by 48% in gray matter (<i>p</i> = 0.002) and by 32% in white matter (<i>p</i> = 0.04). There was a near 40% reduction in NeuN immunoreactivity in microglia in MerTK knock-out mice vs. wild-type (<i>p</i> = 0.03) indicating attenuation of neuronal phagocytosis by microglia. In summary, the reduction in microglial neuronal engulfment and brain injury in MerTK-deficient mice strongly indicates that phagoptosis contributes to neuronal loss after neonatal hypoxia-ischemia. This insight suggests that targeting MerTK-mediated phagocytosis may represent a potential therapeutic approach in neonatal hypoxia-ischemic brain injury.