Spermidine inhibits LPS-induced pro-inflammatory activation of macrophages by acting on Nrf2 signaling but not autophagy

This study was designed to investigate the roles of spermidine on lipopolysaccharide (LPS)-induced macrophage activation and underlying mechanisms. Spermidine was found to induce a moderate activation of autophagy but robust activation of nuclear factor erythroid 2-related factor 2 (Nrf-2) in a murine macrophage cell line RAW264.7 cells. Spermidine blunted LPS-driven proinflammatory activation of RAW264.7 cells evidenced by the reduced release of NO, TNF-alpha, and reactive oxygen species (ROS). The effects of spermidine were not affected by the autophagy inhibitor, while the autophagy inducers could not block the activation of macrophages induced by LPS. Interestingly, Nrf-2 inducers significantly suppressed the secretion of NO and TNF-alpha in RAW264.7 cells exposed to LPS, while the roles of spermidine were significantly blunted by the knockout of Nrf-2. Furthermore, spermidine suppressed the activation of NF-kappa B and the NLRP3 inflammasome in mouse liver. Collectively, spermidine could suppress LPS-induced macrophages activation possibly by activating Nrf-2 in macrophages.