Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury.
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.
Department of Medicine and Arizona Respiratory Center, The University of Arizona.
Sara M
SM
Camp
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago.
Ermelinda
E
Ceco
Department of Medicine and Arizona Respiratory Center, The University of Arizona.
Carrie L
CL
Evenoski
Department of Anesthesiology, University of Illinois at Chicago.
Sergei M
SM
Danilov
Department of Medicine and Arizona Respiratory Center, The University of Arizona.
Tong
T
Zhou
Department of Medicine and Arizona Respiratory Center, The University of Arizona.
Eddie T
ET
Chiang
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago.
Liliana
L
Moreno-Vinasco
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago.
Brandon
B
Mapes
Department of Bioengineering, University of Illinois at Chicago.
Jieling
J
Zhao
Department of Bioengineering, University of Illinois at Chicago.
Gamze
G
Gursoy
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago.
Mary E
ME
Brown
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago.
Djanybek M
DM
Adyshev
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago.
Shahid S
SS
Siddiqui
Department of Medicine and Arizona Respiratory Center, The University of Arizona.
Hector
H
Quijada
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago.
Saad
S
Sammani
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago.
Eleftheria
E
Letsiou
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago.
Laleh
L
Saadat
Life Science Group, Bio-Rad Laboratories, Inc.
Mohammed
M
Yousef
Department of Medicine and Arizona Respiratory Center, The University of Arizona.
Ting
T
Wang
Department of Bioengineering, University of Illinois at Chicago.
Jie
J
Liang
Department of Medicine and Arizona Respiratory Center, The University of Arizona.
Joe G N
JG
Garcia
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D016207:Cytokines / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000276:immunology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000737:chemistry* / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology; D011485:Protein Binding; D011487:Protein Conformation; D051197:Toll-Like Receptor 4 / Q000737:chemistry* / Q000276:immunology*; D055397:Ventilator-Induced Lung Injury / Q000276:immunology*
D016207:Cytokines; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human