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Sci Rep. 2015 Aug 14;5:13135. doi: 10.1038/srep13135.

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

Author information

1
Department of Medicine and Arizona Respiratory Center, The University of Arizona.
2
Institute for Personalized Respiratory Medicine, University of Illinois at Chicago.
3
Department of Anesthesiology, University of Illinois at Chicago.
4
Department of Bioengineering, University of Illinois at Chicago.
5
Life Science Group, Bio-Rad Laboratories, Inc.

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 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.

PMID:
26272519
PMCID:
PMC4536637
DOI:
10.1038/srep13135
[Indexed for MEDLINE]
Free PMC Article

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