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Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells
Jiale Chen, … , Qiang Liu, Jie Zhou
Jiale Chen, … , Qiang Liu, Jie Zhou
Published April 1, 2025
Citation Information: J Clin Invest. 2025;135(7):e183559. https://doi.org/10.1172/JCI183559.
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Research Article Immunology Metabolism

Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells

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Abstract

Newborns exhibit a heightened vulnerability to inflammatory disorders due to their underdeveloped immune system, yet the underlying mechanisms remain poorly understood. Here we report that plasma spermidine is correlated with the maturity of human newborns and reduced risk of inflammation. Administration of spermidine led to the remission of neonatal inflammation in mice. Mechanistic studies revealed that spermidine enhanced the generation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via downstream eIF5A hypusination. Genetic deficiency or pharmacological inhibition of deoxyhypusine synthase (DHPS), a key enzyme of hypusinated eIF5A (eIF5AHyp), diminished the immunosuppressive activity of PMN-MDSCs, leading to aggravated neonatal inflammation. The eIF5AHyp pathway was found to enhance the immunosuppressive function via histone acetylation–mediated epigenetic transcription of immunosuppressive signatures in PMN-MDSCs. These findings demonstrate the spermidine-eIF5AHyp metabolic axis as a master switch to restrict neonatal inflammation.

Authors

Jiale Chen, Lin Zhu, Zhaohai Cui, Yuxin Zhang, Ran Jia, Dongmei Zhou, Bo Hu, Wei Zhong, Jin Xu, Lijuan Zhang, Pan Zhou, Wenyi Mi, Haitao Wang, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou

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Figure 3

Polyamine metabolism is enriched in neonatal myeloid cells.

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Polyamine metabolism is enriched in neonatal myeloid cells.
(A) Polyamin...
(A) Polyamine metabolic pathway. (B–D) The expression of ODC1 (B), DHPS (C), and eIF5AHyp (D) in neutrophils (CD11b+CD14–CD15+LOX1–) from healthy adults (n = 9) and PMN-MDSCs (CD11b+CD14–CD15+LOX1+) from healthy neonates (n = 8) and neonates with inflammation (n = 8) was detected by flow cytometry. Clinical parameters are listed in Supplemental Table 1. (E) The expression of ODC1 and eIF5AHyp in neutrophils from healthy adults and PMN-MDSCs from healthy neonates and neonates with inflammation was detected by immunofluorescence (n = 3 per group; 3 fields of each donor were randomly selected for calculating the mean fluorescence intensity [MFI]). Clinical parameters are listed in Supplemental Table 1. (F) Transcriptional profiling of CD11b+Ly6Clo/–Ly6G+ cells isolated from the spleen of adult mice (AM) and newborn mice (NBM). Heatmaps depict differentially expressed genes involved in polyamine metabolism and transport. (G and H) The expression of ODC1 in CD11b+Ly6Clo/–Ly6G+ cells was detected by flow cytometry (G) (n = 4 per group) and immunofluorescence (H) (n = 3 per group; 3 fields of each donor were randomly selected for calculating the MFI). (I) Cellular polyamines in CD11b+Ly6Clo/–Ly6G+ cells were detected by UPLC-MS/MS (n = 4 per group). Data are shown as mean ± SEM. Statistical analysis was performed using 1-way ANOVA with Tukey’s multiple-comparison test (B–E) and unpaired 2-tailed Student’s t test (G–I). Scale bars: 5 μm. Original magnification, ×2.5 (insets, E and H). *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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