Balance of IL-21 and type I IFN in the granzyme-dependent innate immune response to Staphylococcus aureus

Abstract

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) infection is a major complication of viral respiratory infections and immunodeficient states. Here, we investigated the role of interleukin-21 (IL-21) in host response to pulmonary MRSA infection and unexpectedly found that IL-21 acts directly on neutrophils and can promote MRSA clearance. When administered intra-tracheally into wild-type mice, IL-21 potently induced granzymes and augmented host defense, and IL-21-induced killing of MRSA was also observed with peripheral blood neutrophils from healthy donors but not from patients with autosomal dominant hyper-IgE (Jobs) syndrome. Unexpectedly, however, loss of IL-21 signaling, as occurs in Il21r KO mice or WT mice treated with an IL-21R-Fc fusion protein or mice expressing a mutant STAT3 transgene, also resulted in enhanced clearance of MRSA, and this was associated with enhanced expression of interferon-dependent genes. Moreover, IFNb induced granzyme B expression by neutrophils, and a granzyme B inhibitor blocked IFNb-induced MRSA clearance. These results reveal a balance and an interplay between IL-21 and type-I IFN signaling in the granzyme-dependent neutrophil response to MRSA, indicating that manipulating IL-21 signaling may be a strategy for controlling pulmonary bacterial infections.