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Cited by 180Immune Response and InflammationRespiratory Support and MechanismsNF-κB Signaling Pathways

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

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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 G. N.·2015·Scientific Reports
DOI 10.1038/srep13135PMC PMC4536637
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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 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.

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  • Pretreatment of macrophages with CCR5 and TLR4 blockers partially alleviates rhNAMPT-induced M2 polarization in macrophages.

    “In line with previous reports 70, 71, we pretreated macrophages with C-C chemokine receptor type 5 (CCR5) and Toll-like receptor 4 (TLR4) blockers, which indeed partially alleviated rhNAMPT-induced M2 polarization in macrophages (Figure S7).”

    From Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice (2024) · cites this paper as [71]

    The Results section (‘NAMPT/PBEF is a novel TLR4 agonist triggering NFκB activation’; page unavailable) reports that TLR4 blockers reduced recombinant NAMPT/PBEF-induced NFκB phosphorylation in human lung endothelial cells. It does not report CCR5 blockade or macrophage M2 polarization. The citing sentence presents the M2 result as the citing authors’ own Figure S7 finding, so this source supports the TLR4 rationale, not that result. (LLM, conf=0.88)

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Metadata

Authors
Camp, S. M., Ceco, E., Evenoski, C. L., Danilov, S. M., Zhou, T., Chiang, E. T., Moreno-Vinasco, L., Mapes, B., Zhao, J., Gursoy, G., Brown, M. E., Adyshev, D. M., Siddiqui, S. S., Quijada, H., Sammani, S., Letsiou, E., Saadat, L., Yousef, M., Wang, T., Liang, J., & Garcia, J. G. N.
Affiliations
  • University of Arizona (US)
  • University of Illinois Chicago (US)
  • Bio-Rad (United States) (US)
Corresponding author
Garcia, Joe G. N.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2015-08-14
Volume
5
Issue
1
Pages
13135-13135
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep13135
PMC
PMC4536637
OpenAlex
W2396343210
Cited by
180
References
60
Citations by year
2026: 14 · 2025: 17 · 2024: 21 · 2023: 18 · 2022: 29 · 2021: 18 · 2020: 24 · 2019: 15 · 2018: 11 · 2017: 8 · 2016: 5
FWCI
3.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation (1062328)
  • National Institutes of Health (5p50hl073994-05)
  • National Heart, Lung, and Blood Institute (P50 HL-073994, R01-HL73994, T32HL076139)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
TLR4, MD-2, NF-κB signaling, mechanical stress, innate immunity, lung inflammation, visfatin
MeSH terms
Animals, Binding Sites, Cells, Cultured, Humans, Mice, Inbred C57BL, Models, Chemical, Pneumonia, Protein Binding, Protein Conformation, Cytokines, NF-kappa B, Mice, Knockout, Toll-Like Receptor 4, Mice, Nicotinamide Phosphoribosyltransferase, Ventilator-Induced Lung Injury, Molecular Docking Simulation

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