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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 Article has an altmetric score of 8

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 4

Polyamine-eIF5AHyp enhances the immunosuppressive activity of PMN-MDSCs in neonates.

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Polyamine-eIF5AHyp enhances the immunosuppressive activity of PMN-MDSCs ...
(A and B) Pharmacological inhibition of polyamine metabolism (A) and coculture strategy (B). (C and D) PMN-MDSCs were treated with DFMO (200 μM) for 16 hours. Suppression of T cell proliferation by PMN-MDSCs (C) (n = 5 per group) and expression of eIF5AHyp (D) (n = 4 per group). Data are representative of 3 independent experiments. (E) CD11b+Ly6Clo/–Ly6G+ cells were isolated from adult mice (AM) and newborn mice (NBM). The expression of eIF5AHyp was detected by immunofluorescence (n = 3 per group; 3 fields of each donor were randomly selected for calculating the MFI). Original magnification, ×2.5. (F and G) The expression of eIF5AHyp (F) (n = 4 per group) and hypusination rate (G) (n = 4 per group) in CD11b+Ly6Clo/–Ly6G+ cells of different ages. Data are representative of 3 independent experiments. (H) Suppression of T cell proliferation by PMN-MDSCs, which were pretreated with DMSO, spermidine (SPD) (0.2 μM), GC7 (10 μM), and SPD plus GC7 for 16 hours (n = 6 per group). Data are representative of 3 independent experiments. (I) Suppression of T cell proliferation by Dhpsfl/fl and DhpsΔLysm PMN-MDSCs (n = 6 per group). Data are representative of 3 independent experiments. (J) Bulk RNA sequencing of PMN-MDSCs from the spleen of Dhpsfl/fl and DhpsΔLysm littermates. Heatmaps of differentially expressed genes involved in immunosuppressive function. (K and L) ARG1 (n = 5 per group) and cellular PGE2 production (n = 8 per group) in Dhpsfl/fl and DhpsΔLysm PMN-MDSCs. Data are shown as mean ± SEM. Statistical analysis was performed using 1-way ANOVA with Tukey’s multiple-comparison test (C and I), unpaired 2-tailed Student’s t test (D, E, K, and L), and 2-way ANOVA with Šidák’s multiple-comparison test (H). Scale bar: 5 μm. *P < 0.05, **P < 0.01, ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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