Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates

作者：Xiaogang Zhang, Laiqin Peng, Shuyi Kuang, Tian-Ci Wang, Weibin Wu, Shaowen Zuo, Chunling Chen, Jiaxiu Ye, Guilang Zheng, Yuxiong Guo, Yumei He · 发表于：Journal of Neuroinflammation · 年份：2025 · DOI：10.1186/s12974-025-03385-8 · 被引用次数：11 · 研究领域：Cancer, Hypoxia, and Metabolism、Hyperglycemia and glycemic control in critically ill and hospitalized patients、Mitochondrial Function and Pathology

Fetal intrauterine distress (FD) during delivery can cause fetal intrauterine hypoxia, posing significant risks to the fetus, mother, and newborns. While studies highlight the role of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in neonatal diseases and tumor hypoxia, their specific involvement in newborns experiencing fetal distress during delivery (FDNB) is not well understood. Here, we found elevated PMN-MDSC activation, increased glycolysis, enhanced lactate production, and upregulated HIF-1α expression in the blood of FDNB neonates compared to healthy newborns (NNB). Importantly, PMN-MDSC levels were inversely correlated with neuron-specific enolase (NSE), a marker for neurological injury. In neonatal mice subjected to acute hypoxia, a 48-h exposure led to a shift from exacerbation to amelioration of brain damage when compared with a 24-h period. This change was associated with a reduction in microglial activation, a decrease in the expression of inflammatory factors within the microglia, alongside increased peripheral PMN-MDSC activation. Depleting PMN-MDSCs led to heightened microglial activation and aggravated brain injury. Mechanistically, enhanced activation of PMN-MDSCs promotes HIF-1α accumulation while enhancing glycolysis and lactate release, thereby mitigating neonatal brain injury. Notably, lactate supplementation in hypoxic mice rescued brain damage caused by insufficient PMN-MDSC activation due to HIF-1α deficiency. Our study clarifies the ...