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

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

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

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 NFκ 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 ∼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.

Original languageEnglish (US)
Article number13135
JournalScientific reports
Volume5
DOIs
StatePublished - Aug 14 2015

ASJC Scopus subject areas

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    Camp, S. M., Ceco, E., Evenoski, C. L., Danilov, S. M., Zhou, T., Chiang, E. T., Moreno-Vinasco, L., Mapes, B., Zhao, J., Gursoy, G., Brown, M. E., Adyshev, D. M., Siddiqui, S. S., Quijada, H., Sammani, S., Letsiou, E., Saadat, L., Yousef, M., Wang, T., ... Garcia, J. G. N. (2015). Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκ B Signaling and Inflammatory Lung Injury. Scientific reports, 5, [13135]. https://doi.org/10.1038/srep13135