Farnesoid X Receptor Regulation of the NLRP3 Inflammasome Underlies Cholestasis-Associated Sepsis.
Farnesoid X Receptor Regulation of the NLRP3 Inflammasome Underlies Cholestasis-Associated Sepsis.
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Farnesoid X 受体对 NLRP3 炎性体的调节是胆汁淤积相关脓毒症的基础
DOI：
10.1016/j.cmet.2017.03.007
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发表时间：
2017-04-04
期刊：
影响因子：
29
通讯作者：
Gonzalez FJ
中科院分区：
文献类型：
--
作者：
Hao H;Cao L;Jiang C;Che Y;Zhang S;Takahashi S;Wang G;Gonzalez FJ
胆汁淤积是脓毒症的常见并发症，而血浆胆汁酸水平的升高预示着脓毒症相关的死亡率。然而，胆汁淤积加重脓毒症发展的确切机制仍不清楚。在这里，我们表明胆汁酸是危险相关的分子模式(DAMP)，可以激活炎症巨噬细胞中NLRP3炎症体的信号1和2。从机制上讲，胆汁酸诱导长时间的钙内流，并协同三磷酸腺苷激活NLRP3炎症体。实验性胆汁淤积症使小鼠变得敏感，而胆汁酸隔离剂氯乙四胺则保护小鼠免受脂多糖诱导的脓毒症的影响。FXR通过与NLRP3和caspase 1的物理相互作用负向调节NLRP3炎症体。FXR缺失的小鼠对内氧性休克更敏感，而FXR高表达的小鼠对内氧性休克更具抵抗力。这些发现表明，胆汁酸和FXR通过控制NLRP3炎症小体在脓毒症中发挥关键作用，靶向FXR可能是治疗胆汁淤积性脓毒症的一种策略。胆汁淤积症与脓毒症的高死亡率有关。Hao等人解剖胆汁淤积如何加剧感染性休克进展，并揭示胆汁酸作为阻滞剂同时激活炎症巨噬细胞中NLRP3炎症体的信号1和2。他们进一步表明，FXR负向调节NLRP3的激活。
Cholestasis is a common complication of sepsis, and the increased plasma levels of bile acids are predictive of sepsis-associated mortality. However, the exact mechanism by which cholestasis aggravates sepsis development remains elusive. Here, we show that bile acids are danger-associated molecular patterns (DAMPs) that can activate both signal 1 and 2 of the NLRP3 inflammasome in inflammatory macrophages. Mechanistically, bile acids induce a prolonged calcium influx and activate the NLRP3 inflammasome synergistically with ATP. Experimental cholestasis sensitizes, while cholestyramine, a bile acid sequestrant, protects mice from LPS-induced sepsis. FXR negatively regulates the NLRP3 inflammasome via physical interaction with NLRP3 and caspase 1. Fxr-null mice are more sensitive, while FXR-overexpressing mice are more resistant, to endoxemia shock. These findings suggest that bile acids and FXR play pivotal roles in sepsis via controlling the NLRP3 inflammasome, and that targeting FXR may represent a therapeutic strategy for cholestasis-associated sepsis. Cholestasis is associated with high mortality due to sepsis. Hao et al. dissect how cholestasis potentiates septic shock progression and reveal that bile acids act as DAMPs activating both signal 1 and 2 of the NLRP3 inflammasome in inflammatory macrophages. They further show that FXR negatively regulates NLRP3 activation.
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