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

Sara M. Camp, Ermelinda Ceco, Carrie L. Evenoski, Sergei M. Danilov, Tong Zhou, Eddie T. Chiang, Liliana Moreno-Vinasco, Brandon Mapes, Jieling Zhao, Gamze Gursoy, Mary E. Brown, Djanybek M. Adyshev, Shahid S. Siddiqui, Hector Quijada, Saad Sammani, Eleftheria Letsiou, Laleh Saadat, Mohammed Yousef, Ting Wang, Jie Liang & 1 others Joe GN Garcia

Research output: Contribution to journalArticle

30 Citations (Scopus)

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

Original languageEnglish (US)
Article number13135
JournalScientific Reports
Volume5
DOIs
StatePublished - Aug 14 2015

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Toll-Like Receptor 4
Lung Injury
Ventilator-Induced Lung Injury
Mechanical Stress
Niacinamide
Transferases
Innate Immunity
Biological Availability
Ligation
Pneumonia
Lung
Wounds and Injuries

ASJC Scopus subject areas

  • General

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Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκ B Signaling and Inflammatory Lung Injury. / Camp, Sara M.; Ceco, Ermelinda; Evenoski, Carrie L.; Danilov, Sergei M.; Zhou, Tong; Chiang, Eddie T.; Moreno-Vinasco, Liliana; Mapes, Brandon; Zhao, Jieling; Gursoy, Gamze; Brown, Mary E.; Adyshev, Djanybek M.; Siddiqui, Shahid S.; Quijada, Hector; Sammani, Saad; Letsiou, Eleftheria; Saadat, Laleh; Yousef, Mohammed; Wang, Ting; Liang, Jie; Garcia, Joe GN.

In: Scientific Reports, Vol. 5, 13135, 14.08.2015.

Research output: Contribution to journalArticle

Camp, SM, Ceco, E, Evenoski, CL, Danilov, SM, Zhou, T, Chiang, ET, Moreno-Vinasco, L, Mapes, B, Zhao, J, Gursoy, G, Brown, ME, Adyshev, DM, Siddiqui, SS, Quijada, H, Sammani, S, Letsiou, E, Saadat, L, Yousef, M, Wang, T, Liang, J & Garcia, JGN 2015, 'Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκ B Signaling and Inflammatory Lung Injury', Scientific Reports, vol. 5, 13135. https://doi.org/10.1038/srep13135
Camp, Sara M. ; Ceco, Ermelinda ; Evenoski, Carrie L. ; Danilov, Sergei M. ; Zhou, Tong ; Chiang, Eddie T. ; Moreno-Vinasco, Liliana ; Mapes, Brandon ; Zhao, Jieling ; Gursoy, Gamze ; Brown, Mary E. ; Adyshev, Djanybek M. ; Siddiqui, Shahid S. ; Quijada, Hector ; Sammani, Saad ; Letsiou, Eleftheria ; Saadat, Laleh ; Yousef, Mohammed ; Wang, Ting ; Liang, Jie ; Garcia, Joe GN. / Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκ B Signaling and Inflammatory Lung Injury. In: Scientific Reports. 2015 ; Vol. 5.
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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 (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.",
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AU - Danilov, Sergei M.

AU - Zhou, Tong

AU - Chiang, Eddie T.

AU - Moreno-Vinasco, Liliana

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AU - Zhao, Jieling

AU - Gursoy, Gamze

AU - Brown, Mary E.

AU - Adyshev, Djanybek M.

AU - Siddiqui, Shahid S.

AU - Quijada, Hector

AU - Sammani, Saad

AU - Letsiou, Eleftheria

AU - Saadat, Laleh

AU - Yousef, Mohammed

AU - Wang, Ting

AU - Liang, Jie

AU - Garcia, Joe GN

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