Abstract
Although IL-17A (commonly referred to as IL-17) has been implicated in the pathogenesis of central nervous system (CNS) autoimmune disease, its role during CNS bacterial infections remains unclear. To evaluate the broader impact of IL-17 family members in the context of CNS infection, we utilized IL-17 receptor (IL-17R) knockout (KO) mice that lack the ability to respond to IL-17, IL-17F and IL-17E (IL-25). In this article, we demonstrate that IL-17R signaling regulates bacterial clearance as well as natural killer T (NKT) cell and gamma-delta (γδ) T cell infiltrates during Staphylococcus aureus-induced brain abscess formation. Specifically, when compared with wild-type (WT) animals, IL-17R KO mice exhibited elevated bacterial burdens at days 7 and 14 following S. aureus infection. Additionally, IL-17R KO animals displayed elevated neutrophil chemokine production, revealing the ability to compensate for the lack of IL-17R activity. Despite these differences, innate immune cell recruitment into brain abscesses was similar in IL-17R KO and WT mice, whereas IL-17R signaling exerted a greater influence on adaptive immune cell recruitment. In particular, γδ T cell influx was increased in IL-17R KO mice at day 7 post-infection. In addition, NK1.1high infiltrates were absent in brain abscesses of IL-17R KO animals and, surprisingly, were rarely detected in the livers of uninfected IL-17R KO mice. Although IL-17 is a key regulator of neutrophils in other infection models, our data implicate an important role for IL-17R signaling in regulating adaptive immunity during CNS bacterial infection.
Highlights
Brain abscesses typically develop following parenchymal colonization with pyogenic bacteria, such as Staphylococcus aureus or streptococcus strains [1,2]
It was expected that IL-17 family members would be an essential component in the developing immune response to S. aureus brain abscesses, since IL-17A and IL-17E are known to play a role in granulopoiesis, neutrophil recruitment, and proinflammatory cytokine production in response to extracellular bacterial infections [40,41]
To investigate the functional importance of IL-17 signaling in the context of central nervous system (CNS) infection, brain abscess pathogenesis was evaluated in IL-17 receptor (IL-17R) KO and WT mice
Summary
Brain abscesses typically develop following parenchymal colonization with pyogenic bacteria, such as Staphylococcus aureus or streptococcus strains [1,2]. Characterized by an acute edematous response, S. aureus abscesses begin as localized areas of inflammation, evolving into suppurative lesions surrounded by a fibrotic capsule. Brain abscesses are still associated with significant morbidity and mortality [3]. Long-term morbidity issues arise in patients recovering from these infections as a result of the extensive parenchymal damage typically associated with brain abscess formation, which can manifest as seizures, cognitive deficits, and/. A better understanding of the complex host-pathogen interactions that occur during brain abscess formation is essential for the development of novel therapies to treat these devastating infections
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