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

IF 9.3 1区 医学 Q1 IMMUNOLOGY
Xiaogang Zhang, Laiqin Peng, Shuyi Kuang, Tianci Wang, Weibin Wu, Shaowen Zuo, Chunling Chen, Jiaxiu Ye, Guilang Zheng, Yuxiong Guo, Yumei He
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Abstract

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.

分娩过程中的胎儿宫内窘迫(FD)可导致胎儿宫内缺氧,给胎儿、母亲和新生儿带来重大风险。虽然研究强调了多形核髓鞘源性抑制细胞(PMN-MDSCs)在新生儿疾病和肿瘤缺氧中的作用,但它们在经历分娩期胎儿窘迫(FDNB)的新生儿中的具体参与情况还不十分清楚。在这里,我们发现与健康新生儿(NNB)相比,胎儿窘迫新生儿血液中的 PMN-MDSC 活性升高、糖酵解增加、乳酸生成增强以及 HIF-1α 表达上调。重要的是,PMN-MDSC 水平与神经元特异性烯醇化酶(NSE)成反比,NSE 是神经损伤的标志物。在遭受急性缺氧的新生小鼠中,与 24 小时暴露相比,48 小时暴露导致脑损伤从加重转为改善。这种变化与小胶质细胞活化减少、小胶质细胞内炎症因子表达减少以及外周 PMN-MDSC 活化增加有关。消耗 PMN-MDSCs 会导致小胶质细胞活化增强,加重脑损伤。从机制上讲,PMN-MDSCs 的活化增强会促进 HIF-1α 的积累,同时增强糖酵解和乳酸盐的释放,从而减轻新生儿脑损伤。值得注意的是,在缺氧小鼠体内补充乳酸盐可挽救因缺乏HIF-1α而导致的PMN-MDSC活化不足所造成的脑损伤。我们的研究阐明了乳酸盐在急性缺氧后外周PMN-MDSCs中的作用及其对小胶质细胞活化和随后脑损伤的影响。
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来源期刊
Journal of Neuroinflammation
Journal of Neuroinflammation 医学-神经科学
CiteScore
15.90
自引率
3.20%
发文量
276
审稿时长
1 months
期刊介绍: The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.
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