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

• Published in: Scientific reports Vol. 5; no. 1; p. 13135
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 14.08.2015
• Subjects: Animals; Binding Sites; Cells, Cultured; Cytokines - chemistry; Cytokines - immunology; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Chemical; Molecular Docking Simulation; NF-kappa B - immunology; Nicotinamide Phosphoribosyltransferase - chemistry; Nicotinamide Phosphoribosyltransferase - immunology; Pneumonia - immunology; Protein Binding; Protein Conformation; Toll-Like Receptor 4 - chemistry; Toll-Like Receptor 4 - immunology; Ventilator-Induced Lung Injury - immunology
• ISSN: 2045-2322; 2045-2322
• 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 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.