1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
Download icon

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
  • Views 1,054
  • Annotations
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.

Metrics

  • 1,054
    Page views
  • 155
    Downloads
  • 2
    Citations

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

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)

Categories and tags

Research organism

Further reading

    1. Developmental Biology
    2. Immunology and Inflammation

    A functional screen of RNA binding proteins identifies genes that promote or limit the accumulation of CD138+ plasma cells

    David J Turner et al.
    Short Report Updated

    To identify roles of RNA binding proteins (RBPs) in the differentiation or survival of antibody secreting plasma cells we performed a CRISPR/Cas9 knockout screen of 1213 mouse RBPs for their ability to affect proliferation and/or survival, and the abundance of differentiated CD138 + cells in vitro. We validated the binding partners CSDE1 and STRAP as well as the m6A binding protein YTHDF2 as promoting the accumulation of CD138 + cells in vitro. We validated the EIF3 subunits EIF3K and EIF3L and components of the CCR4-NOT complex as inhibitors of CD138 + cell accumulation in vitro. In chimeric mouse models YTHDF2-deficient plasma cells failed to accumulate.

    1. Immunology and Inflammation
    2. Neuroscience

    Single-cell profiling reveals periventricular CD56bright NK cell accumulation in multiple sclerosis

    Sabela Rodríguez-Lorenzo et al.
    Research Article

    Multiple sclerosis (MS) is a chronic demyelinating disease characterised by immune cell infiltration resulting in lesions that preferentially affect periventricular areas of the brain. Despite research efforts to define the role of various immune cells in MS pathogenesis, the focus has been on a few immune cell populations while full-spectrum analysis, encompassing others such as natural killer (NK) cells, has not been performed. Here, we used single-cell mass cytometry (CyTOF) to profile the immune landscape of brain periventricular areas - septum and choroid plexus – and of the circulation from donors with MS, dementia and controls without neurological disease. Using a 37-marker panel, we revealed the infiltration of T cells and antibody-secreting cells in periventricular brain regions and identified a novel NK cell signature specific to MS. CD56bright NK cells were accumulated in the septum of MS donors and displayed an activated and migratory phenotype, similar to that of CD56bright NK cells in the circulation. We validated this signature by multiplex immunohistochemistry and found that the number of NK cells with high expression of granzyme K, typical of the CD56bright subset, was increased in both periventricular lesions and the choroid plexus of donors with MS. Together, our multi-tissue single-cell data shows that CD56bright NK cells accumulate in the periventricular brain regions of MS patients, bringing NK cells back to the spotlight of MS pathology.

    1. Immunology and Inflammation
    2. Stem Cells and Regenerative Medicine

    Endothelial SIRPα signaling controls VE-cadherin endocytosis for thymic homing of progenitor cells

    Boyang Ren et al.
    Research Article

    Thymic homing of hematopoietic progenitor cells (HPCs) is tightly regulated for proper T cell development. Previously we have identified a subset of specialized thymic portal endothelial cells (TPECs), which is important for thymic HPC homing. However, the underlying molecular mechanism still remains unknown. Here, we found that signal regulatory protein alpha (SIRPα) is preferentially expressed on TPECs. Disruption of CD47-SIRPα signaling in mice resulted in reduced number of thymic early T cell progenitors (ETPs), impaired thymic HPC homing, and altered early development of thymocytes. Mechanistically, Sirpa-deficient ECs and Cd47-deficient bone marrow progenitor cells or T lymphocytes demonstrated impaired transendothelial migration (TEM). Specifically, SIRPα intracellular ITIM motif-initiated downstream signaling in ECs was found to be required for TEM in an SHP2- and Src-dependent manner. Furthermore, CD47 signaling from migrating cells and SIRPα intracellular signaling were found to be required for VE-cadherin endocytosis in ECs. Thus, our study reveals a novel role of endothelial SIRPα signaling for thymic HPC homing for T cell development.