Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NF kappa B Signaling and Inflammatory Lung Injury

作者：Camp Sara M; Ceco Ermelinda; Evenoski Carrie L; Danilov Sergei M; Zhou Tong; Chiang Eddie T; Moreno Vinasco Liliana; Mapes Brandon; Zhao Jieling; Gursoy Gamze; Brown Mary E; Adyshev Djanybek M; Siddiqui Shahid S; Quijada Hector; Sammani Saad; Letsiou Eleftheria; Saadat Laleh; Yousef Mohammed; Wang Ting; Liang Jie; Garcia Joe G N^*

来源：Scientific Reports, 2015, 5(1): 13135.

DOI：10.1038/srep13135

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 NF kappa B 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 similar to 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.

• 出版日期2015-8-14