STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression
STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression
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DOI：
10.1038/s41467-020-17669-5
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发表时间：
2020-07-30
影响因子：
16.6
通讯作者：
Mansell, Ashley
中科院分区：
文献类型：
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作者：
Balic, Jesse J.;Albargy, Hassan;Mansell, Ashley
通过巨噬细胞上的Toll样受体4(TLR4)检测微生物成分，如脂多糖(LPS)，可以诱导依赖于代谢重编程的强大的促炎反应。这些先天代谢变化被比作肿瘤细胞中的有氧糖酵解。然而，TLR4激活导致线粒体和糖酵解重编程的机制尚不清楚。在这里，我们发现TLR4的激活诱导了一个招募TRAF6和Tbk-1的信号级联反应，而Tbk-1则在S727上磷酸化了STAT3。使用不能进行STAT3Ser727磷酸化的基因工程小鼠模型，我们在体内和体外证明了STAT3Ser727磷酸化在脂多糖诱导的炎症模型中对于糖酵解重编程、中枢免疫反应代谢物琥珀酸的产生和炎性细胞因子的产生至关重要。我们的研究发现，非典型的STAT3激活是TLR4诱导的糖酵解、巨噬细胞代谢重编程和炎症的关键信号媒介。TLR4信号可以重新编程巨噬细胞的新陈代谢，使其更具糖酵解和促炎作用。在这里，作者证明了内毒素和TLR4信号导致TBK1的募集，进而使STAT3上的丝氨酸727磷酸化，通过影响线粒体代谢来实现促炎开关。
Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) on macrophages induces a robust pro-inflammatory response that is dependent on metabolic reprogramming. These innate metabolic changes have been compared to aerobic glycolysis in tumour cells. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming are unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, production of the central immune response metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation. TLR4 signalling can reprogram the metabolism of macrophages to be more glycolytic and proinflammatory. Here the authors show that LPS and TLR4 signalling results in recruitment of TBK1, which in turn phosphorylates serine 727 on STAT3 to enable a proinflammatory switch via an effect on mitochondrial metabolism.