Lactate accumulation from HIF-1alpha-mediated PMN-MDSCs glycolysis restricts brain injury after acute hypoxia in neonates.
Fetal intrauterine distress (FD) during delivery leads to fetal intrauterine hypoxia, which is harmful to the fetus, pregnant mother, and newborns. Various studies have highlighted the vital role of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in neonatal diseases and tumor hypoxia, their role in newborns with fetal distress during delivery (FDNB) and the underlying mechanisms remain unclear. Increased activation of PMN-MDSCs was observed in FDNB neonate blood, as well as enhanced glycolysis, lactate production, and HIF-1 alpha expression in PMN-MDSCs. Importantly, PMN-MDSC levels had a significant negative correlation with neurologic injury assessment markers. Additionally, the brain injury in neonatal mice shifted from exacerbation to alleviation after acute hypoxia, accompanied by a shift in microglia polarization from M1 to M2, and an increase activation of peripheral PMN-MDSCs. Depletion of PMN-MDSCs exacerbated brain injury and caused a shift in microglia polarization from M2 to M1. Mechanistically, enhanced activation of peripheral PMN-MDSCs promotes accumulation of HIF-1 alpha protein, facilitates glycolysis and lactate release, thereby alleviating neonatal brain injury. Notably, lactate supplementation in hypoxic mice can rescue brain damage caused by insufficient PMN-MDSC activation due to HIF-1 alpha deficiency. This study underscores the role of a lactate in peripheral PMN-MDSCs post-acute hypoxia in influencing microglia cell polarization and brain injury.