Spermidine Dampens Inflammation by Directly Inhibiting Th17 Cytokine Production through a PRDX1 Associated Antioxidant Pathway

The activation of IL-17 signaling has been linked to the pathogenesis of many chronic, inflammatory lung diseases including cystic fibrosis. Through unbiased single-cell RNAseq screening, we found that IL-17+ T cells highly express Srm and Smox, which encode two key enzymes involved in spermidine synthesis, spermidine synthase and spermine oxidase respectively. Spermidine has been shown to reduce inflammation by regulating macrophage activation and balancing Th17/Treg differentiation; however its direct effects on Th17 cytokine production have not been carefully investigated. Here, using already differentiated Th17 cells from cultured mouse splenocytes, we found that exogenous spermidine directly inhibits IL-1β/IL-23-induced IL-17 production. Blockade of endogenous spermidine synthesis enhanced IL-17 production above native levels, further supporting the notion that spermidine is a direct regulator of cytokine secretion independent of differentiation. In vivo, spermidine alleviates lung inflammation in both Pseudomonas aeruginosa (PA) and LPS induced acute lung injury models. Further RNA-seq analysis suggests that spermidine suppression of Th17 cytokine production is mediated through its PRDX1-dependent antioxidant activity. Our data suggests that spermidine is a direct regulator of Type-17 T cell cytokine production and has potent anti-inflammatory effects against lung inflammation.