Delinking CARD9 and IL-17: CARD9 Protects against Candida tropicalis Infection through a TNF-α-Dependent, IL-17-Independent Mechanism.
Bottom Line: Consistently, WT mice depleted of TNF-α were more susceptible to C. tropicalis, and CARD9-deficient neutrophils and monocytes failed to produce TNF-α following stimulation with C. tropicalis Ags.However, TNF-α treatment of neutrophils in vitro enhanced their ability to kill C. tropicalis.Moreover, CARD9-dependent production of TNF-α enhances the candidacidal capacity of neutrophils, limiting fungal disease during disseminated C. tropicalis infection.
Affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;Show MeSH
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Mentions: TNF-α is produced rapidly upon disseminated C. albicans infection and is required for host defense (47, 48). Monocytes are prominent producers of TNF-α, although this cytokine can potentially be produced by many cell types, including neutrophils (49). Given the rapid mortality of infected CARD9−/− mice and the requirement for neutrophils and monocytes in this setting, we hypothesized that TNF-α production by these cell types is important for host defense against C. tropicalis. To test this hypothesis, we first measured TNF-α production by WT and CARD9−/− bone marrow neutrophils and monocytes that were stimulated with HK C.t in vitro. Strikingly, CARD9−/− neutrophils and monocytes were completely defective in TNF-α production following HK C.t stimulation (Fig. 4A). To determine whether CARD9−/− neutrophils and monocytes were impaired in TNF-α production during C. tropicalis infection, we assessed TNF-α levels in the blood of WT and CARD9−/− mice by flow cytometry on days 2 and 5. In line with in vitro data, both neutrophils and monocytes isolated from the blood of CARD9−/− mice on days 2 and 5 were severely impaired in TNF-α production in response to HK C.t compared with WT mice (Fig. 4B–E). Thus, CARD9 mediates the production of TNF-α by neutrophils and monocytes during disseminated C. tropicalis infection.
Affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;