IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus
- National Heart, Lung, and Blood Institute, United States
- National Institute of Allergy and Infectious Diseases, Netherlands
- 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.
Article and author information
Author details
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.
Reviewing Editor
- Wayne M Yokoyama, Washington University School of Medicine, United States
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.
Version history
- Received: January 24, 2019
- Accepted: April 9, 2019
- Accepted Manuscript published: April 10, 2019 (version 1)
- Accepted Manuscript updated: April 16, 2019 (version 2)
- 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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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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