Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury.
Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury.
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DOI：
10.1038/srep13135
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发表时间：
2015-08-14
影响因子：
4.6
通讯作者：
Garcia JG
中科院分区：
文献类型：
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作者：
Camp SM;Ceco E;Evenoski CL;Danilov SM;Zhou T;Chiang ET;Moreno-Vinasco L;Mapes B;Zhao J;Gursoy G;Brown ME;Adyshev DM;Siddiqui SS;Quijada H;Sammani S;Letsiou E;Saadat L;Yousef M;Wang T;Liang J;Garcia JG
呼吸机诱导的炎性肺损伤（VILI）与NAMPT转录和烟酰胺磷酸核糖基转移酶（NAMPT/PBEF）循环水平增加在机制上相关。尽管VILI的严重程度因NAMPT/PBEF生物利用度降低而减弱，但NAMPT/PBEF和过度机械应力对VILI病理生物学的确切贡献尚不清楚。我们现在报道NAMPT/PBEF通过直接连接Toll样受体4（TLR 4）诱导肺NFκB转录活性和炎症损伤。计算分析表明，NAMPT/PBEF和MD-2（LPS诱导的TLR 4活化所必需的TLR 4结合蛋白）共享约30%的序列同一性，并且在MD-2-TLR 4结合的关键环区域中表现出惊人的结构相似性。与MD-2不同，MD-2的TLR 4单独结合不足以启动TLR 4信号传导，NAMPT/PBEF单独产生稳健的TLR 4活化，可能是通过与LPS结构相似的NAMPT/PBEF的突出区域（S402-N412）。通过NAMPT/PBEF识别这种独特的TLR 4激活模式，促进了对先天免疫应答以及与机械应力诱导的肺部炎症相关的不良事件的理解。
Ventilator-induced inflammatory lung injury (VILI) is mechanistically linked to increased NAMPT transcription and circulating levels of nicotinamide phosphoribosyl-transferase (NAMPT/PBEF). Although VILI severity is attenuated by reduced NAMPT/PBEF bioavailability, the precise contribution of NAMPT/PBEF and excessive mechanical stress to VILI pathobiology is unknown. We now report that NAMPT/PBEF induces lung NFκB transcriptional activities and inflammatory injury via direct ligation of Toll–like receptor 4 (TLR4). Computational analysis demonstrated that NAMPT/PBEF and MD-2, a TLR4-binding protein essential for LPS-induced TLR4 activation, share ~30% sequence identity and exhibit striking structural similarity in loop regions critical for MD-2-TLR4 binding. Unlike MD-2, whose TLR4 binding alone is insufficient to initiate TLR4 signaling, NAMPT/PBEF alone produces robust TLR4 activation, likely via a protruding region of NAMPT/PBEF (S402-N412) with structural similarity to LPS. The identification of this unique mode of TLR4 activation by NAMPT/PBEF advances the understanding of innate immunity responses as well as the untoward events associated with mechanical stress-induced lung inflammation.