Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells
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
- Wenyi Mi (ORCID: https://orcid.org/0000-0002-7453-051X)
- Jie Zhou (ORCID: https://orcid.org/0000-0001-5964-1599)
- Zhaohai Cui (ORCID: https://orcid.org/0000-0003-0208-6648)
- Zhi Yao (ORCID: https://orcid.org/0000-0003-1382-225X)
- Yuxin Zhang (ORCID: https://orcid.org/0009-0004-6159-9309)
- Qiang Liu (ORCID: https://orcid.org/0000-0002-9134-0160)
- Lijuan Zhang (ORCID: https://orcid.org/0009-0001-7156-1759)
- Jin Xu (ORCID: https://orcid.org/0000-0001-8764-7541)
- Jiale Chen (ORCID: https://orcid.org/0000-0003-1781-9744)
- Bo Hu (ORCID: https://orcid.org/0000-0003-1462-8854)
- Dongmei Zhou (ORCID: https://orcid.org/0000-0003-0163-8164)
- Pan Zhou (ORCID: https://orcid.org/0000-0002-7105-6808)
- Lin Zhu (ORCID: https://orcid.org/0000-0003-2272-5769)
- Ran Jia
- Ying Yu (ORCID: https://orcid.org/0000-0002-6476-1752)
- Wei Zhong (ORCID: https://orcid.org/0000-0003-2917-4832)
- Haitao Wang (ORCID: https://orcid.org/0000-0002-2965-4441)
Institutions
- Tianjin Medical University General Hospital (CN)
- Children's Hospital of Fudan University (CN)
- Tianjin Medical University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-03-31
- DOI
- https://doi.org/10.1172/jci183559
- Primary Topic
- Antimicrobial Peptides and Activities
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China