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 can exert multiple effects on neutrophils and monocytes. For example, TNF-α acts upon nonhematopoietic cells to induce production of chemokines that recruit neutrophils, such as CXCL1, CXCL2, and CXCL5 (50–53). In this regard, defective neutrophil recruitment in CARD9−/− mice was demonstrated in Aspergillus fumigatus infection (54, 55). Additionally, TNF-α can signal directly in neutrophils and monocytes to enhance killing of C. albicans and other fungi (56, 57). To evaluate neutrophil activity during C. tropicalis infection, we measured expression of neutrophil-attracting chemokines in kidneys of infected mice. Expression of Cxcl1, Cxcl2, and Cxcl5 was not detected until day 5 postinfection but was similar between WT and CARD9−/− mice (Fig. 5A). These results hinted that recruitment of neutrophils was unlikely to be impaired in C. tropicalis–infected CARD9−/− mice. To confirm this hypothesis, we measured the expansion and recruitment of neutrophils in the blood and kidneys during infection. An increase in both the percentage and absolute numbers of neutrophils was observed at 12 h in blood of infected WT and CARD9−/− mice (Fig. 5C, 5D). A decrease in neutrophils at day 1 was followed by a second wave of expansion at day 2 in both WT and CARD9−/− mice (Fig. 5B–D). At day 5, neutrophil levels remained unchanged. In the kidneys, no detectable difference in neutrophil numbers was seen at day 1 postinfection (Fig. 5F). However, an increase in neutrophils was detected at day 2 in both infected WT and CARD9−/− mice, and neutrophils were further expanded at day 5 (Fig. 5E, 5F). Notably, neutrophil numbers in the kidneys of CARD9−/− mice exceeded those in WT kidneys at day 5, suggesting overzealous neutrophil responses in CARD9−/− mice at this later time point.
Affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;