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Delinking CARD9 and IL-17: CARD9 Protects against Candida tropicalis Infection through a TNF-α-Dependent, IL-17-Independent Mechanism.

Whibley N, Jaycox JR, Reid D, Garg AV, Taylor JA, Clancy CJ, Nguyen MH, Biswas PS, McGeachy MJ, Brown GD, Gaffen SL - J. Immunol. (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;

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Neutrophil expansion and recruitment to the kidneys are not impaired in CARD9−/− mice during C. tropicalis infection. (A) WT and CARD9−/− kidneys were harvested on the indicated days, and gene expression was assessed by quantitative PCR. Data are representative of two experiments (n = 4–10 mice). Bar graphs show mean ± SEM. Blood (B–D) and kidneys (E and F) were analyzed by flow cytometry for CD45+CD11b+Ly6G+ neutrophils at the indicated time points postinfection. Data were pooled from two to six experiments (n = 4–20 mice/time point). Cells were gated through leukocyte, single cell, live cell, and CD45+ gates. *p < 0.05, **p < 0.01, Kruskal–Wallis and post hoc Dunn multiple-comparisons tests.
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fig05: Neutrophil expansion and recruitment to the kidneys are not impaired in CARD9−/− mice during C. tropicalis infection. (A) WT and CARD9−/− kidneys were harvested on the indicated days, and gene expression was assessed by quantitative PCR. Data are representative of two experiments (n = 4–10 mice). Bar graphs show mean ± SEM. Blood (B–D) and kidneys (E and F) were analyzed by flow cytometry for CD45+CD11b+Ly6G+ neutrophils at the indicated time points postinfection. Data were pooled from two to six experiments (n = 4–20 mice/time point). Cells were gated through leukocyte, single cell, live cell, and CD45+ gates. *p < 0.05, **p < 0.01, Kruskal–Wallis and post hoc Dunn multiple-comparisons tests.

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.


Delinking CARD9 and IL-17: CARD9 Protects against Candida tropicalis Infection through a TNF-α-Dependent, IL-17-Independent Mechanism.

Whibley N, Jaycox JR, Reid D, Garg AV, Taylor JA, Clancy CJ, Nguyen MH, Biswas PS, McGeachy MJ, Brown GD, Gaffen SL - J. Immunol. (2015)

Neutrophil expansion and recruitment to the kidneys are not impaired in CARD9−/− mice during C. tropicalis infection. (A) WT and CARD9−/− kidneys were harvested on the indicated days, and gene expression was assessed by quantitative PCR. Data are representative of two experiments (n = 4–10 mice). Bar graphs show mean ± SEM. Blood (B–D) and kidneys (E and F) were analyzed by flow cytometry for CD45+CD11b+Ly6G+ neutrophils at the indicated time points postinfection. Data were pooled from two to six experiments (n = 4–20 mice/time point). Cells were gated through leukocyte, single cell, live cell, and CD45+ gates. *p < 0.05, **p < 0.01, Kruskal–Wallis and post hoc Dunn multiple-comparisons tests.
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fig05: Neutrophil expansion and recruitment to the kidneys are not impaired in CARD9−/− mice during C. tropicalis infection. (A) WT and CARD9−/− kidneys were harvested on the indicated days, and gene expression was assessed by quantitative PCR. Data are representative of two experiments (n = 4–10 mice). Bar graphs show mean ± SEM. Blood (B–D) and kidneys (E and F) were analyzed by flow cytometry for CD45+CD11b+Ly6G+ neutrophils at the indicated time points postinfection. Data were pooled from two to six experiments (n = 4–20 mice/time point). Cells were gated through leukocyte, single cell, live cell, and CD45+ gates. *p < 0.05, **p < 0.01, Kruskal–Wallis and post hoc Dunn multiple-comparisons tests.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;

Show MeSH
Related in: MedlinePlus