IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus
Rosanne Spolski,
Erin E West,
Peng Li,
Sharon Veenbergen,
Sunny Yung,
Majid Kazemian,
Jangsuk Oh,
Zu-Xi Yu,
Alexandra F Freeman,
Stephen M Holland,
Philip M Murphy,
Warren J Leonard
Affiliations
Rosanne Spolski
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States; Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
Erin E West
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States; Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
Peng Li
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States; Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
Sharon Veenbergen
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
Sunny Yung
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States; Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
Jangsuk Oh
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States; Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
Zu-Xi Yu
The Pathology Core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States
Alexandra F Freeman
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
Stephen M Holland
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
Philip M Murphy
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States; Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
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 also 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 IFNβ 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.
