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

TitleUnique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury.
Publication TypeJournal Article
Year of Publication2015
AuthorsCamp 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 JGN
JournalSci Rep
Date Published2015 Aug 14
ISSN Number2045-2322
KeywordsAnimals, Binding Sites, Cells, Cultured, Cytokines, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Chemical, Molecular Docking Simulation, NF-kappa B, Nicotinamide Phosphoribosyltransferase, Pneumonia, Protein Binding, Protein Conformation, Toll-Like Receptor 4, Ventilator-Induced Lung Injury

<p>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.</p>

Alternate JournalSci Rep
PubMed ID26272519
PubMed Central IDPMC4536637
Grant ListP50 HL073994 / HL / NHLBI NIH HHS / United States
T32 HL076139 / HL / NHLBI NIH HHS / United States
R01HL73994 / HL / NHLBI NIH HHS / United States