TY - JOUR TI - IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus AU - Spolski, Rosanne AU - West, Erin E AU - Li, Peng AU - Veenbergen, Sharon AU - Yung, Sunny AU - Kazemian, Majid AU - Oh, Jangsuk AU - Yu, Zu-Xi AU - Freeman, Alexandra F AU - Holland, Stephen M AU - Murphy, Philip M AU - Leonard, Warren J A2 - Yokoyama, Wayne M A2 - Garrett, Wendy S A2 - Verhoef, Philip VL - 8 PY - 2019 DA - 2019/04/10 SP - e45501 C1 - eLife 2019;8:e45501 DO - 10.7554/eLife.45501 UR - https://doi.org/10.7554/eLife.45501 AB - 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. KW - methicillin-resistant Staph aureus KW - IL-21 KW - neutrophil JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -