IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus

  1. Rosanne Spolski  Is a corresponding author
  2. Erin E West
  3. Peng Li
  4. Sharon Veenbergen
  5. Sunny Yang
  6. Majid Kazemian
  7. Jangsuk Oh
  8. Zu-Xi Yu
  9. Alexandra Freeman
  10. Stephen Holland
  11. Philip M Murphy
  12. Warren J Leonard  Is a corresponding author
  1. National Heart, Lung, and Blood Institute, United States
  2. National Institute of Allergy and Infectious Diseases, Netherlands
  3. National Institute of Allergy and Infectious Diseases, United States

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a major hospital- and community-acquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intra-tracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils. Unexpectedly, however, basal MRSA clearance was enhanced when IL-21 signaling was blocked, both in Il21r KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This correlated with increased type I interferon and an IFN-related gene signature, and indeed anti-IFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFNb induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These results reveal an interplay between IL-21 and type-I IFN in the innate immune response to MRSA.

Data availability

All sequencing data in the final manuscript will be deposited in GEO.

The following data sets were generated

Article and author information

Author details

  1. Rosanne Spolski

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    For correspondence
    spolskir@nhlbi.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
  2. Erin E West

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Peng Li

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sharon Veenbergen

    Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Sunny Yang

    Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Majid Kazemian

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7080-8820
  7. Jangsuk Oh

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Zu-Xi Yu

    The Pathology Core, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Alexandra Freeman

    Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Stephen Holland

    Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Philip M Murphy

    Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Warren J Leonard

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    For correspondence
    wjl@helix.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5740-7448

Funding

National Institutes of Health (Division of Intramural Research, NHLBI)

  • Warren J Leonard

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

Ethics

Animal experimentation: Experiments involving animals were performed under protocols (H-0087R4) approved by the National Heart, Lung, and Blood Institute Animal Care and Use Committee and followed National Institutes of Health guidelines for use of animals in intramural research.

Human subjects: Blood samples were obtain from normal donors from the NIH Blood Bank under a waiver from the NIH Office of Human Subjects research. Blood samples were also obtained from AD-HIES patients who had given informed consent under an NIH IRB-approved protocol.

Reviewing Editor

  1. Wayne M Yokoyama, Washington University School of Medicine, United States

Publication history

  1. Received: January 24, 2019
  2. Accepted: April 9, 2019
  3. Accepted Manuscript published: April 10, 2019 (version 1)
  4. Accepted Manuscript updated: April 16, 2019 (version 2)
  5. Version of Record published: May 7, 2019 (version 3)

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.

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  1. Rosanne Spolski
  2. Erin E West
  3. Peng Li
  4. Sharon Veenbergen
  5. Sunny Yang
  6. Majid Kazemian
  7. Jangsuk Oh
  8. Zu-Xi Yu
  9. Alexandra Freeman
  10. Stephen Holland
  11. Philip M Murphy
  12. Warren J Leonard
(2019)
IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus
eLife 8:e45501.
https://doi.org/10.7554/eLife.45501

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    Funding:

    Supported by KL2 career development grant by Miami CTSI under NIH Award UL1TR002736, Stanley Glaser Foundation, American College of Surgeons Franklin Martin Career Development Award, and Association for Academic Surgery Joel J. Roslyn Faculty Award (to J. Datta); NIH R01 CA161976 (to N.B. Merchant); and NCI/NIH Award P30CA240139 (to J. Datta and N.B. Merchant).

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