Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκ B 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 NFκ B 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.