Spermidine restricts neonatal inflammation via metabolic shaping of PMN-MDSCs

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 (eIF5AHyp). Genetic deficiency or pharmacological inhibition of deoxyhypusine synthase (DHPS), a key enzyme of eIF5AHyp, diminished the immunosuppressive activity of PMN-MDSCs, leading to aggravated neonatal inflammation. The eIF5AHyp pathway was found to enhance mitochondrial function via histone acetylation-mediated epigenetic transcription of immunosuppressive signatures in PMN-MDSCs. These findings demonstrated spermidine-eIF5AHyp metabolic axis as a master switch to restrict neonatal inflammation.