Distinct metabolic programs, either energy-consuming anabolism or energy-generating catabolism, were required for different biological functions. Macrophages can adopt different immune phenotypes in response to various cues and exhibit anti- or pro-inflammatory properties relying on catabolic pathways associated with oxidative phosphorylation (OXPHOS) or glycolysis. Spermidine, a natural polyamine, has been reported to regulate inflammation through inducing anti-inflammatory (M2) macrophages. However, the underlying mechanisms remain elusive. We show here that the M2-polarization induced by spermidine is mediated by mitochondrial reactive oxygen species (mtROS). The levels of mitochondrial superoxide and H₂O₂ were markedly elevated by spermidine. Mechanistically, mtROS were found to activate AMP-activated protein kinase (AMPK), which in turn enhanced mitochondrial function. Furthermore, hypoxia-inducible factor-1α (Hif-1α) was upregulated by the AMPK activation and mtROS and was required for the expression of anti-inflammatory genes and induction of autophagy. Consistent with previous report that autophagy is required for the M2 polarization, we found that the M2 polarization induced by spermidine was also mediated by increased autophagy. The macrophages treated with spermidine in vitro were found to ameliorate Dextran Sulfate Sodium (DSS)-induced inflammatory bowel disease (IBD) in mice. Thus, spermidine can elicit an anti-inflammatory program driven by mtROS-dependent AMPK activation, Hif-1α stabilization and autophagy induction in macrophages. Our studies revealed a critical role of mtROS in shaping macrophages into M2-like phenotype and provided novel information for management of inflammatory disease by spermidine.

不同的生物学功能需要不同的代谢程序，无论是消耗能量的合成代谢还是产生能量的分解代谢。巨噬细胞可根据各种提示采取不同的免疫表型，并依赖于与氧化磷酸化（OXPHOS）或糖酵解相关的分解代谢途径表现出抗炎或促炎特性。据报道，亚精胺是一种天然的多胺，可通过诱导抗炎（M2）巨噬细胞来调节炎症。但是，基本机制仍然难以捉摸。我们在这里显示亚精胺诱导的M2极化是由线粒体活性氧（mtROS）介导的。线粒体超氧化物和H ₂ O _2的水平被亚精胺明显升高。从机理上讲，人们发现mtROS可以激活AMP激活的蛋白激酶（AMPK），进而增强线粒体功能。此外，AMPK激活和mtROS会上调缺氧诱导因子1α（Hif-1α），这是表达抗炎基因和诱导自噬所必需的。与以前的报告称自噬是M2极化所必需的，我们发现亚精胺诱导的M2极化也由自噬的增加介导。发现用亚精胺体外处理的巨噬细胞可改善小鼠葡聚糖硫酸钠（DSS）诱导的炎症性肠病（IBD）。因此，亚精胺可以在巨噬细胞中引发由mtROS依赖性AMPK激活，Hif-1α稳定和自噬诱导驱动的抗炎程序。