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.
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).
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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Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RA−CCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3−CCR7+Helios−CD127−CD8+) and pro-inflam Macs (CD206−CD163−CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163−CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206− pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.
