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

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 1

Plasma spermidine is correlated with a reduced risk of inflammation in human newborns.

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Plasma spermidine is correlated with a reduced risk of inflammation in h...
(A) Plasma polyamines in healthy adults (n = 10) and neonates (n = 13) were determined by UPLC-MS/MS. Clinical parameters are listed in Supplemental Table 1. SPD, spermidine; PUT, putrescine; SPM, spermine. (B–G) Plasma samples were collected from healthy neonates within 2 days of birth, and clinical parameters are listed in Supplemental Table 2. Polyamines and I-FABP2 were detected by ELISA. (B) Schematic approach for plasma sample collection. (C–F) Correlation between SPD and gestational age (C), birth weight (D), C-reactive protein (CRP) (E), and I-FABP2 (F). The infants were divided into 2 groups based on the presence of subsequent inflammatory disorders within 1 month of follow-up: the inflammation group and the non-inflammation group. (G) SPD concentration in inflammation group (Infla) (n = 42) and non-inflammation group (Non-infla) (n = 41). (H) Plasma SPD concentration in healthy full-term babies (n = 8), preterm babies (n = 11), and necrotizing enterocolitis (NEC) patients (n = 14). Clinical parameters are listed in Supplemental Table 1. Data are shown as mean ± SEM. Statistical analysis was performed using unpaired 2-tailed Student’s t test (A and G), Spearman’s correlation coefficient (C–F), and 1-way ANOVA with Tukey’s multiple-comparison test (H). *P < 0.05, **P < 0.01, ***P < 0.001.