Neutrophil dynamics, plasticity and function in acute neurodegeneration following neonatal hypoxia-ischemia

Neonatal encephalopathy following hypoxia-ischemia (HI) is a major cause of long-term morbidity and mortality in children. Even though HI-induced neuroinflammation, involving infiltration of peripheral immune cells into the CNS has been associated with disease pathogenesis, the specific role of neutrophils is highly debated. Due to immaturity of the neonatal immune system, it has been assumed that neutrophils are less clinically relevant in neonatal HI-induced brain injury. In the present study, we demonstrate that neutrophils are rapidly activated in the neonatal brain after exposure to experimental HI, revealed by an enhanced proportion of CD86(+) cells and an increased expression of CD11b compared to splenic and blood neutrophils. Furthermore, production of reactive oxygen species and the proportion of hyperactivated/aged (CXCR4(+)CD62L(-)) cells was enhanced in brain compared to peripheral neutrophils. Delayed neutrophil depletion, initiated 12 h after HI resulted in reduced cellular neurodegeneration, associated with reduced microand astroglial activation. In the present study, we uncovered a new complex switch of the phenotype in brain neutrophils, which may offer new possibilities for the development of selective therapeutic approaches by modulation of neutrophils in the early post-hypoxic disease phase.

Automated summary

This study found that neutrophils in the neonatal brain are rapidly activated after experimental hypoxia-ischemia, producing reactive oxygen species and showing an increased proportion of hyperactivated/aged cells compared to peripheral neutrophils. Delayed neutrophil depletion led to reduced cellular neurodegeneration and decreased microglial and astroglial activation, offering new possibilities for therapeutic approaches in post-hypoxic brain injury.