TLR5 participates in the TLR4 receptor complex and promotes MyD88-dependent signaling in environmental lung injury

  1. Salik Hussain
  2. Collin G Johnson
  3. Joseph Sciurba
  4. Xianglin Meng
  5. Vandy P Stober
  6. Caini Liu
  7. Jaime M Cyphert-Daly
  8. Katarzyna Bulek
  9. Wen Qian
  10. Alma Solis
  11. Yosuke Sakamachi
  12. Carol S Trempus
  13. Jim J Aloor
  14. Kym M Gowdy
  15. W Michael Foster
  16. John W Hollingsworth
  17. Robert M Tighe
  18. Xiaoxia Li
  19. Michael B Fessler
  20. Stavros Garantziotis  Is a corresponding author
  1. National Institute of Environmental Health Sciences, United States
  2. First Affiliated Hospital of Harbin Medical University, China
  3. Cleveland Clinic Foundation, United States
  4. East Carolina University Brody School of Medicine, United States
  5. Duke University Medical Center, United States

Abstract

Lung disease causes significant morbidity and mortality, and is exacerbated by environmental injury, e.g. through lipopolysaccharide (LPS) or ozone (O3). Toll-like receptors (TLRs) orchestrate immune responses to injury by recognizing pathogen- or danger-associated molecular patterns. TLR4, the prototypic receptor for LPS, also mediates inflammation after O3, triggered by endogenous hyaluronan. Regulation of TLR4 signaling is incompletely understood. TLR5, the flagellin receptor, is expressed in alveolar macrophages, and regulates immune responses to environmental injury. Using in vivo animal models of TLR4-mediated inflammations (LPS, O3, hyaluronan), we show that TLR5 impacts the in vivo response to LPS, hyaluronan and O3. We demonstrate that immune cells of human carriers of a dominant negative TLR5 allele have decreased inflammatory response to O3 exposure ex vivo and LPS exposure in vitro. Using primary murine macrophages, we find that TLR5 physically associates with TLR4 and biases TLR4 signaling towards the MyD88 pathway. Our results suggest an updated paradigm for TLR4/TLR5 signaling.

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Author details

  1. Salik Hussain

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Collin G Johnson

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Joseph Sciurba

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Xianglin Meng

    Department of ICU, First Affiliated Hospital of Harbin Medical University, Harbin, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Vandy P Stober

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Caini Liu

    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jaime M Cyphert-Daly

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Katarzyna Bulek

    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8064-7047
  9. Wen Qian

    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Alma Solis

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Yosuke Sakamachi

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Carol S Trempus

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Jim J Aloor

    East Carolina University Brody School of Medicine, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kym M Gowdy

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. W Michael Foster

    Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. John W Hollingsworth

    Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Robert M Tighe

    Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Xiaoxia Li

    Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4872-9525
  19. Michael B Fessler

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Stavros Garantziotis

    National Institute of Environmental Health Sciences, Research Triangle Park, United States
    For correspondence
    garantziotis@niehs.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4007-375X

Funding

National Institute of Environmental Health Sciences (Z01ES102605)

  • Stavros Garantziotis

National Institute of Environmental Health Sciences (Z01ES102005)

  • Michael B Fessler

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Mice were given access to water and chow ad libitum, and were maintained at a 12-hour dark-light cycle. All experiments are approved by the NIEHS Institutional Animal Care and Use Committee.

Human subjects: All subjects signed informed consent and all clinical research protocols were approved by the IRBs at Duke University Medical Center and the National Institute of Environmental Health Sciences, as applicable. The study described herein is using data collected as part of several clinical or translational studies (NCT01087307, NCT00341237, NCT00574158) and were approved by NIEHS and Duke IRBs (Protocol IRB approvals # 10-E-0063, 04-E-0053, 12496-CP-004)

Reviewing Editor

  1. Jos WM van der Meer, Radboud University Medical Centre, Netherlands

Publication history

  1. Received: July 23, 2019
  2. Accepted: January 24, 2020
  3. Accepted Manuscript published: January 28, 2020 (version 1)
  4. Version of Record published: February 20, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Salik Hussain
  2. Collin G Johnson
  3. Joseph Sciurba
  4. Xianglin Meng
  5. Vandy P Stober
  6. Caini Liu
  7. Jaime M Cyphert-Daly
  8. Katarzyna Bulek
  9. Wen Qian
  10. Alma Solis
  11. Yosuke Sakamachi
  12. Carol S Trempus
  13. Jim J Aloor
  14. Kym M Gowdy
  15. W Michael Foster
  16. John W Hollingsworth
  17. Robert M Tighe
  18. Xiaoxia Li
  19. Michael B Fessler
  20. Stavros Garantziotis
(2020)
TLR5 participates in the TLR4 receptor complex and promotes MyD88-dependent signaling in environmental lung injury
eLife 9:e50458.
https://doi.org/10.7554/eLife.50458
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