Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome
- NYU School of Medicine, United States
- BD Life Sciences, United States
- Benaroya Research Institute at Virginia Mason, United States
- MD Anderson, United States
- University of Miami Miller School of Medicine, United States
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.
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Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome, Dryad, DatasetDryad Digital Repository, doi:10.5061/dryad.b5mkkwhcv.
Article and author information
Author details
Stephanie S Watowich
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.
Reviewing Editor
- Russell E Vance, University of California, Berkeley, United States
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).
Version history
- Received: March 13, 2021
- Preprint posted: April 23, 2021 (view preprint)
- Accepted: August 10, 2021
- Accepted Manuscript published: August 11, 2021 (version 1)
- Version of Record published: August 19, 2021 (version 2)
- 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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Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome
eLife 10:e68371.
https://doi.org/10.7554/eLife.68371
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