1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
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Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome

  1. Isabelle J Marie  Is a corresponding author
  2. Lara Brambilla
  3. Doua Azzouz
  4. Ze Chen
  5. Gisele V Baracho
  6. Azlann Arnett
  7. Haiyan S Li
  8. Weiguo Liu
  9. Lluisa Cimmino
  10. Pratip Chattopadhyay
  11. Gregg Silverman
  12. Stephanie S Watowich
  13. Bernard Khor
  14. David Levy  Is a corresponding author
  1. NYU School of Medicine, United States
  2. BD Life Sciences, United States
  3. Benaroya Research Institute at Virginia Mason, United States
  4. MD Anderson, United States
  5. University of Miami Miller School of Medicine, United States
Research Article
  • Cited 2
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Cite this article as: eLife 2021;10:e68371 doi: 10.7554/eLife.68371

Abstract

Maintenance of immune homeostasis involves a synergistic relationship between the host and the microbiome. Canonical interferon (IFN) signaling controls responses to acute microbial infection, through engagement of the STAT1 transcription factor. However, the contribution of tonic levels of IFN to immune homeostasis in absence of acute infection remains largely unexplored. We report that STAT1 KO mice spontaneously developed an inflammatory disease marked by myeloid hyperplasia and splenic accumulation of hematopoietic stem cells. Moreover, these animals developed inflammatory bowel disease. Profiling gut bacteria revealed a profound dysbiosis in absence of tonic IFN signaling, which triggered expansion of TH17 cells and loss of splenic Treg cells. Reduction of bacterial load by antibiotic treatment averted the TH17 bias, and blocking IL17 signaling prevented myeloid expansion and splenic stem cell accumulation. Thus, tonic IFNs regulate gut microbial ecology, which is crucial for maintaining physiologic immune homeostasis and preventing inflammation.

Data availability

Sequencing data related to microbiome analysis have been deposited in Dryad at http://dx.doi.org/10.5061/dryad.b5mkkwhcvSource data files for other figures are provided with the manuscript.

The following data sets were generated

Article and author information

Author details

  1. Isabelle J Marie

    Pathology, NYU School of Medicine, New York, United States
    For correspondence
    Isabelle.Marie@nyulangone.org
    Competing interests
    No competing interests declared.
  2. Lara Brambilla

    Pathology, NYU School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  3. Doua Azzouz

    Pathology and Medicine, NYU School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  4. Ze Chen

    Medicine, NYU School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  5. Gisele V Baracho

    Immunology, BD Life Sciences, La Jolla, United States
    Competing interests
    Gisele V Baracho, Gisele Baracho is affiliated with BD Life Sciences. The author has no financial interests to declare.
  6. Azlann Arnett

    Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, United States
    Competing interests
    No competing interests declared.
  7. Haiyan S Li

    Immunology, MD Anderson, Houston, United States
    Competing interests
    No competing interests declared.
  8. Weiguo Liu

    Pathology, NYU School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  9. Lluisa Cimmino

    Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States
    Competing interests
    No competing interests declared.
  10. Pratip Chattopadhyay

    Medicine, NYU School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  11. Gregg Silverman

    Pathology and Medicine, NYU School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  12. Stephanie S Watowich

    Immunology, MD Anderson, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1969-659X
  13. Bernard Khor

    Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4689-5092
  14. David Levy

    Pathology and Microbiology, NYU School of Medicine, New York, United States
    For correspondence
    david.levy@med.nyu.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7320-7788

Funding

National Institutes of Health (A!28900)

  • Isabelle J Marie
  • David Levy

National Institutes of Health (AI133822)

  • Stephanie S Watowich

National Institutes of Health (AR070591)

  • Gregg Silverman

National Institutes of Health (CA016087)

  • Pratip Chattopadhyay

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

Ethics

Animal experimentation: All animals used in these experiments were maintained in a single dedicated room of a specific pathogen-free vivarium at NYU Grossman School of Medicine. All work with experimental animals was in accordance with protocols approved by the NYU Langone Health Institutional Animal Care and Use Committee (IACUC ID: IA16-01579).

Reviewing Editor

  1. Russell E Vance, University of California, Berkeley, United States

Publication history

  1. Received: March 13, 2021
  2. Preprint posted: April 23, 2021 (view preprint)
  3. Accepted: August 10, 2021
  4. Accepted Manuscript published: August 11, 2021 (version 1)
  5. Version of Record published: August 19, 2021 (version 2)
  6. Version of Record updated: August 23, 2021 (version 3)

Copyright

© 2021, Marie et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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