1. Immunology and Inflammation
Download icon

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
Research Article
  • Cited 20
  • Views 2,268
  • Annotations
Cite this article as: eLife 2020;9:e50458 doi: 10.7554/eLife.50458

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.

Data availability

Source data files have been provided

Article and author information

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.

Metrics

  • 2,268
    Page views
  • 316
    Downloads
  • 20
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Immunology and Inflammation
    Riem Gawish et al.
    Research Article

    In silico modelling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNg and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Thomas Laval et al.
    Research Article Updated

    Successful control of Mycobacterium tuberculosis (Mtb) infection by macrophages relies on immunometabolic reprogramming, where the role of fatty acids (FAs) remains poorly understood. Recent studies unraveled Mtb’s capacity to acquire saturated and monounsaturated FAs via the Mce1 importer. However, upon activation, macrophages produce polyunsaturated fatty acids (PUFAs), mammal-specific FAs mediating the generation of immunomodulatory eicosanoids. Here, we asked how Mtb modulates de novo synthesis of PUFAs in primary mouse macrophages and whether this benefits host or pathogen. Quantitative lipidomics revealed that Mtb infection selectively activates the biosynthesis of ω6 PUFAs upstream of the eicosanoid precursor arachidonic acid (AA) via transcriptional activation of Fads2. Inhibiting FADS2 in infected macrophages impaired their inflammatory and antimicrobial responses but had no effect on Mtb growth in host cells nor mice. Using a click-chemistry approach, we found that Mtb efficiently imports ω6 PUFAs via Mce1 in axenic culture, including AA. Further, Mtb preferentially internalized AA over all other FAs within infected macrophages by mechanisms partially depending on Mce1 and supporting intracellular persistence. Notably, IFNγ repressed de novo synthesis of AA by infected mouse macrophages and restricted AA import by intracellular Mtb. Together, these findings identify AA as a major FA substrate for intracellular Mtb, whose mobilization by innate immune responses is opportunistically hijacked by the pathogen and downregulated by IFNγ.