Zhang Xiaogang, Peng Laiqin, Kuang Shuyi, Wang Tianci, Wu Weibin, Zuo Shaowen, Chen Chunling, Ye Jiaxiu, Zheng Guilang, Guo Yuxiong, He Yumei
Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Department of Immunology, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
J Neuroinflammation. 2025 Mar 1;22(1):59. doi: 10.1186/s12974-025-03385-8.
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 role of lactate in peripheral PMN-MDSCs after acute hypoxia and its effects on microglial activation and subsequent brain injury.
分娩期间的胎儿宫内窘迫（FD）可导致胎儿宫内缺氧，对胎儿、母亲和新生儿构成重大风险。虽然研究强调了多形核髓源性抑制细胞（PMN-MDSCs）在新生儿疾病和肿瘤缺氧中的作用，但其在分娩期间经历胎儿窘迫的新生儿（FDNB）中的具体作用尚不清楚。在这里，我们发现与健康新生儿（NNB）相比，FDNB新生儿血液中PMN-MDSC的激活增加、糖酵解增强、乳酸生成增加以及HIF-1α表达上调。重要的是，PMN-MDSC水平与神经损伤标志物神经元特异性烯醇化酶（NSE）呈负相关。在遭受急性缺氧的新生小鼠中，与24小时的暴露时间相比，48小时的暴露导致脑损伤从加重转变为改善。这种变化与小胶质细胞激活的减少、小胶质细胞内炎症因子表达的降低以及外周PMN-MDSC激活的增加有关。耗尽PMN-MDSCs会导致小胶质细胞激活增强和脑损伤加重。从机制上讲，PMN-MDSCs的增强激活促进HIF-1α的积累，同时增强糖酵解和乳酸释放，从而减轻新生儿脑损伤。值得注意的是，在缺氧小鼠中补充乳酸可挽救因HIF-1α缺乏导致PMN-MDSC激活不足而引起的脑损伤。我们的研究阐明了急性缺氧后乳酸在外周PMN-MDSCs中的作用及其对小胶质细胞激活和随后脑损伤的影响。
