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 journalArticlepeer-review

105 Scopus citations


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
StatePublished - Aug 14 2015

ASJC Scopus subject areas

  • General


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