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

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 NFκ B transcriptional activities and inflammatory injury via direct ligation of Toll-like receptor 4 (TLR 4). Computational analysis demonstrated that NAMPT/PBEF and MD -2, a TLR4-binding protein essential for LPS-induced TLR 4 activation, share ∼30% sequence identity and exhibit striking structural similarity in loop regions critical for MD -2 -TLR 4 binding. Unlike MD -2, whose TLR 4 binding alone is insufficient to initiate TLR4 signaling, NAMPT/PBEF alone produces robust TLR 4 activation, likely via a protruding region of NAMPT/PBEF (S 402 -N 412) with structural similarity to LPS. The identification of this unique mode of TLR 4 activation by NAMPT/PBEF advances the understanding of innate immunity responses as well as the untoward events associated with mechanical stress-induced lung inflammation.