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.
View: Text | PDF
Research Article Immunology Metabolism Article has an altmetric score of 8

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

×

Figure 5

eIF5AHyp maintains the mitochondrial function of neonatal PMN-MDSCs by modulating translation of NFU1.

Options: View larger image (or click on image) Download as PowerPoint
eIF5AHyp maintains the mitochondrial function of neonatal PMN-MDSCs by m...
(A and B) After treatment with GC7 (10 μM) for 16 hours, PMN-MDSCs were collected for proteomics analysis using LC-MS/MS. Volcano plot of all proteins (A) and KEGG analysis (B). (C) After treatment with GC7 (10 μM) for 16 hours, PMN-MDSCs were collected for targeted metabolomics. (D) Mitochondrial membrane potential of Dhpsfl/fl and DhpsΔLysm PMN-MDSCs treated with or without succinate (Suc; 1 μM) was evaluated with tetramethylrhodamine methyl ester (TMRM) by flow cytometry (n = 4 per group). Data are representative of 3 independent experiments. (E) Oxygen consumption rate (OCR) of Dhpsfl/fl and DhpsΔLysm PMN-MDSCs treated with or without succinate was evaluated by Seahorse assay (n = 3 per group). (F) Suppression of T cell proliferation by Dhpsfl/fl and DhpsΔLysm PMN-MDSCs, which were pretreated with citrate (Citr; 1 μM) and succinate (Suc; 1 μM) (n = 6 per group). Data are representative of 3 independent experiments. (G) Target sequences were inserted into N-terminus of DsRed and separated by a GSGSG flexible linker. Transfection was evaluated by green fluorescent protein (GFP), and translation was quantified as the ratio of DsRed to GFP. (H) Transfected NIH 3T3 cells were treated with GC7 (10 μM) for 24 hours. Expression of DsRed and GFP was measured by flow cytometry (n = 5 per group). Data are representative of 3 independent experiments. (I) Suppression of T cell proliferation by PMN-MDSCs. Nfu1 was silenced by Nfu1-shRNA followed by treatment with GC7 (10 μM) (n = 6 per group). Data are representative of 3 independent experiments. Data are shown as mean ± SEM. Statistical analysis was performed using 1-way ANOVA with Tukey’s multiple-comparison test (D–F) and 2-way ANOVA with Šidák’s multiple-comparison test (H and I). NS, P > 0.05; *P < 0.05, **P < 0.01, ***P < 0.001.