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.
Highlights
Ventilator-induced inflammatory lung injury (VILI) is mechanistically linked to increased NAMPT transcription and circulating levels of nicotinamide phosphoribosyl-transferase (NAMPT/pre-B cell colony-enhancing factor (PBEF))
NAMPT/PBEF expression is markedly elevated in acutely inflamed lungs in acute respiratory distress syndrome (ARDS) and VILI10,12, in cardiac tissues during cardiac arrest and resuscitation[31], in amniotic membranes during gestation[32] and is released from visceral fat during the development of obesity, an observation resulting in its naming as visfatin[9]
We recently demonstrated that NAMPT expression in the lung is transcriptionally regulated by excessive mechanical stress via STAT5-dependent increases in NAMPT promoter activity[10,33] and via post-transcriptional epigenetic mechanisms involving 5′ UTR promoter demethylation and 3′ UTR miRNA binding[33,34]
Summary
Ventilator-induced inflammatory lung injury (VILI) is mechanistically linked to increased NAMPT transcription and circulating levels of nicotinamide phosphoribosyl-transferase (NAMPT/PBEF). 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. NAMPT regulates intracellular nicotinamide adenine dinucleotide (NAD) biosynthesis and apoptosis pathways[11,13,14,15] It is the increased NAMPT/PBEF expression and extracellular secretion into blood and bronchoalveolar lavage fluid that produce the profound inflammatory effects of NAMPT/ PBEF in response to inflammatory stimuli such as excessive mechanical stress[10,12]. Contributing to potential mechanisms of NAMPT/PBEF-mediated lung pathobiology, we demonstrated that exogenous NAMPT/PBEF elicits robust inflammatory gene transcription in murine lungs[12], including dysregulated genes in the transcriptome related to leukocyte extravasation, the transcription factor NFκ B12, and expression of Toll-like receptors (TLR)[12,16]
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