Spermidine Suppresses Inflammatory DC Function by Activating the FOXO3 Pathway and Counteracts Autoimmunity
Spermidine Suppresses Inflammatory DC Function by Activating the FOXO3 Pathway and Counteracts Autoimmunity
复制标题
亚精胺通过激活 FOXO3 通路抑制炎症 DC 功能并对抗自身免疫
DOI：
10.1016/j.isci.2019.100807
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发表时间：
2020-01-24
期刊：
影响因子：
5.8
通讯作者：
Shen, Nan
中科院分区：
文献类型：
--
作者：
Li, Guanhua;Ding, Huihua;Shen, Nan
树突状细胞（DCS）功能与微环境和代谢密切相关。 I型干扰素（IFNS）条件树突状细胞会对弱的自我信号反应，从而导致自身免疫性。但是，该过程中的代谢适应性尚不清楚。在这里，我们将精子定为影响DC代谢适应性的关键代谢产物。首先，动态代谢组筛查表明，在IFN启动过程中和TLR7配体刺激后，精子量减少，并伴随着从氧化磷酸化到糖酵解的代谢变化。其次，精子补充剂限制了糖酵解，并防止了体内和体外的IFN-alpha启动DC的过度激活。第三，机制研究发现，FOXO3的活性适应了代谢变化，介导精子的抗炎作用。更重要的是，在体内添加精子可以极大地缓解小鼠类似牛皮癣的症状的发展。因此，我们的研究揭示了代谢变化增强了直流反应，并将精子定为自身免疫性疾病的潜在治疗剂。
Dendritic cells (DCs) function is intimately linked to microenvironment and metabolism. Type I interferons (IFNs) condition dendritic cells to respond to weak self-signals, leading to autoimmunity. However, the metabolic adaption in the process is unclear. Here, we identified spermidine as a critical metabolite impacting the metabolic fitness of DC. First, dynamic metabolome screening indicated that spermidine decreased during IFN priming and following TLR7 ligand stimulation, accompanied by metabolic change from oxidative phosphorylation to glycolysis. Second, spermidine supplement restrained the glycolysis and prevented the overactivation of IFN-alpha primed DC both in vivo and in vitro. Third, mechanism study uncovered that the activity of FOXO3 adapted to the metabolic change, mediating the anti-inflammatory effect of spermidine. More importantly, addition of spermidine in vivo greatly alleviated the development of psoriasis-like symptom in mice. Thus, our studies revealed metabolic changes boosting DC responses and identified spermidine as a potential therapeutic agent for autoimmune diseases.