Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates
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, thei...
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BMC
2025-03-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-025-03385-8 |
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| author | Xiaogang Zhang Laiqin Peng Shuyi Kuang Tianci Wang Weibin Wu Shaowen Zuo Chunling Chen Jiaxiu Ye Guilang Zheng Yuxiong Guo Yumei He |
| author_facet | Xiaogang Zhang Laiqin Peng Shuyi Kuang Tianci Wang Weibin Wu Shaowen Zuo Chunling Chen Jiaxiu Ye Guilang Zheng Yuxiong Guo Yumei He |
| author_sort | Xiaogang Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e42287157d50486f91b1073a1d0d0536 |
| institution | OA Journals |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-e42287157d50486f91b1073a1d0d05362025-08-20T02:16:45ZengBMCJournal of Neuroinflammation1742-20942025-03-0122112610.1186/s12974-025-03385-8Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonatesXiaogang Zhang0Laiqin Peng1Shuyi Kuang2Tianci Wang3Weibin Wu4Shaowen Zuo5Chunling Chen6Jiaxiu Ye7Guilang Zheng8Yuxiong Guo9Yumei He10Pediatric Intensive Care Unit, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Department of Immunology, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Gynecology and Obstetrics, Huizhou Central People’s HospitalDepartment of Immunology, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Immunology, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Neonatology, Nanfang Hospital, Southern Medical UniversityDepartment of Immunology, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical UniversityPediatric Intensive Care Unit, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University; Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences,Department of Gynecology and Obstetrics, Huizhou Central People’s HospitalPediatric Intensive Care Unit, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University; Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences,Pediatric Intensive Care Unit, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University; Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences,Pediatric Intensive Care Unit, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Department of Immunology, School of Basic Medical Sciences, Southern Medical UniversityAbstract 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.https://doi.org/10.1186/s12974-025-03385-8Fetal intrauterine distressPolymorphonuclear myeloid-derived suppressor cellsHIF-1αGlycolysisLactateMicroglial activation |
| spellingShingle | Xiaogang Zhang Laiqin Peng Shuyi Kuang Tianci Wang Weibin Wu Shaowen Zuo Chunling Chen Jiaxiu Ye Guilang Zheng Yuxiong Guo Yumei He Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates Journal of Neuroinflammation Fetal intrauterine distress Polymorphonuclear myeloid-derived suppressor cells HIF-1α Glycolysis Lactate Microglial activation |
| title | Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates |
| title_full | Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates |
| title_fullStr | Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates |
| title_full_unstemmed | Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates |
| title_short | Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates |
| title_sort | lactate accumulation from hif 1α mediated pmn mdsc glycolysis restricts brain injury after acute hypoxia in neonates |
| topic | Fetal intrauterine distress Polymorphonuclear myeloid-derived suppressor cells HIF-1α Glycolysis Lactate Microglial activation |
| url | https://doi.org/10.1186/s12974-025-03385-8 |
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