Abstract
Invasive fungal infections by Candida albicans frequently cause mortality in immunocompromised patients. Neutrophils are particularly important for fungal clearance during systemic C. albican infection, yet little has been known regarding which surface receptor controls neutrophils’ antifungal activities. CD137, which is encoded by Tnfrsf9, belongs to the tumor necrosis receptor superfamily and has been shown to regulate neutrophils in Gram-positive bacterial infection. Here, we used genetic and immunological tools to probe the involvement of neutrophil CD137 signaling in innate defense mechanisms against systemic C. albicans infection. We first found that Tnfrsf9−/− mice were susceptible to C. albicans infection, whereas injection of anti-CD137 agonistic antibody protected the host from infection, suggesting that CD137 signaling is indispensable for innate immunity against C. albicans infection. Priming of isolated neutrophils with anti-CD137 antibody promoted their phagocytic and fungicidal activities through phospholipase C. In addition, injection of anti-CD137 antibody significantly augmented restriction of fungal growth in Tnfrsf9−/− mice that received wild-type (WT) neutrophils. In conclusion, our results demonstrate that CD137 signaling contributes to defense mechanisms against systemic C. albicans infection by promoting rapid fungal clearance.
Highlights
To assess the function of CD137 signaling during systemic C. albicans infection, wildtype (WT) and Tnfrsf9−/− C57BL/6 mice were infected with 3 × 105 colony-forming units (CFUs) C. albicans per mouse
Pretreatment of U73122, a phospholipase inhibitor, dividual neutrophils’. These results suggest that abrogated the effect of anti-CD137 antibody on neutrophils’ phagocytic activitiesCD137 to a signaling only 4B), broadened the that poolCD137 of neutrophils capacity, and large extentnot
Fungicidal assays demonstrated that phagocytosed C. albicans were killed more rapidly inside neutrophils primed by anti-CD137 antibody (Figure 4D), suggesting that priming with anti-CD137 antibody elevated the killing activity of neutrophils
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Neutrophils represent a major group of effector cells that are critical for defense against invasive fungal infection [1,2]. They employ various strategies to restrict fungi, including the machinery for capturing and killing, such as various cytotoxic enzymes and their products, neutrophil extracellular traps (NETs), and phagocytic receptors [2]
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