IL-21 regulates the innate immune response to Staphylococcus aureus pulmonary infection.

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) infection is a major complication of viral respiratory infections and immunodeficient states. Although the innate immune response mediated by neutrophils plays a major role in the clearance of MRSA, the cytokine regulation of this process is poorly understood. Here, we investigated the role of IL-21 in the host response to pulmonary MRSA infection. In experiments using a mouse model, Il21r-deficient mice more efficiently cleared pulmonary MRSA infection, suggesting a negative role for IL-21 in MRSA clearance. Interestingly, Il21r KO mice displayed an enhanced “interferon signature” response after pulmonary MRSA infection as compared to WT mice, and blocking the type I IFN response eliminated the ability of Il21r KO mice to more efficiently clear the infection. Despite the more efficient clearing of pulmonary MRSA in Il21r KO than in wild-type mice, when IL-21 was administered to wild-type mice, there was enhanced clearance of MRSA, and this clearance was accompanied by the induction of cytolytic proteases and other components of pulmonary defense. Correspondingly, human peripheral blood neutrophils responded directly to IL-21 with the induction of cytolytic proteases including granzymes, and they displayed enhanced IL-21-induced killing of MRSA that was granzyme-dependent. These data demonstrate that although the chronic absence of IL-21 signaling in Il21r KO leads to the dominant action of type I IFN responses that result in MRSA clearance, IL-21 directly induces a cytolytic program in both human and mouse neutrophils that results in MRSA killing. These data suggest that manipulation of IL-21 signaling may be a strategy for controlling bacterial infections.