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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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 2

Spermidine attenuates neonatal inflammation.

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Spermidine attenuates neonatal inflammation. (A–E) Spermidine (SPD) for ...
(A–E) Spermidine (SPD) for treating NEC. (A) Schematic approach for supplementation of SPD (10 mg/kg/d) during NEC induction. PND, postnatal day. (B) Survival curve of mice after induction of NEC (PBS, n = 21; SPD, n = 20). Data combined from 2 independent experiments. (C) H&E staining and histopathological scores of intestinal tissues (n = 6 per group). (D) Relative mRNA expression of Il1b, Tnfa, and Il10 was determined by quantitative real-time PCR (n = 6 per group). (E) Bacterial abundance in the intestinal wall was evaluated by 16S abundance (n = 6 per group). (F–I) SPD for treating neonatal endotoxemia. (F) Schematic approach for supplementation of SPD (10 mg/kg/d); endotoxemia was induced by intraperitoneal injection of LPS (15 mg/kg). (G) Survival curve of mice after induction of endotoxemia (n = 16 per group). Data combined from 2 independent experiments. (H) H&E staining and histopathological scores of lung, liver, and kidney (n = 5 per group). (I) Relative mRNA expression of Il1b, Tnfa, and Il10 was determined by quantitative real-time PCR (n = 5 per group). Data are shown as mean ± SEM. Statistical analysis was performed using log-rank (Mantel-Cox) test (B and G) and unpaired 2-tailed Student’s t test (C–E, H, and I). Scale bars: 100 μm. *P < 0.05, **P < 0.01, ***P < 0.001.