Human dendritic cells are less potent at killing Candida albicans than both monocytes and macrophages

Netea, Mihai G.; Gijzen, Karlijn; Coolen, Neeltje A.; Verschueren, Ineke; Figdor, Carl G.; Meer, J.W.M. van der; Torensma, Ruurd; Kullberg, Bart Jan

doi:10.1016/j.micinf.2004.05.013

Cited by 56 publications

(47 citation statements)

References 16 publications

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Section: Discussionsupporting

confidence: 91%

“…These results are consistent with reports showing that Candida is poorly killed by DC [25], but not with other studies indicating that this yeast is efficiently killed by DC [49]. These discrepancies could be due to differences in the methodology as discussed by Netea et al [25].We also found that stimulation with PMA enhances DC fungicidal activity by inducing ROS production. It is worth to point out that, although it is not a physiological agonist, PMA directly activates the protein kinase C-dependent phosphorylation of NADPH oxidase components, thus reproducing the final step of NADPH oxidase activation by a large number of physiological stimulators of this enzyme [11].…”

supporting

confidence: 91%

“…albicans influences some functions of human DC [22][23][24][25][26]. Therefore, we investigated whether Candida affects the NADPH oxidase activity of DC.…”

Section: Albicans Inhibits Nadph Oxidase Activitymentioning

confidence: 99%

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NADPH oxidase of human dendritic cells: Role in Candida albicans killing and regulation by interferons, dectin‐1 and CD206

et al. 2007

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Human monocyte-derived DC express the enzyme NADPH oxidase, responsible for ROS production. We show that Candida albicans did not activate NADPH oxidase in DC, and was poorly killed by these cells. However, Candida-killing activity increased upon DC stimulation with the NADPH oxidase activator PMA and was further enhanced by DC treatment with IFN-a or IFN-c. This fungicidal activity took place at high DC-to-Candida ratio, but decreased at low DC-to-yeast ratio, when Candida inhibited the NADPH oxidase by contrasting the assembly of the enzyme on DC plasma membrane. The NADPH oxidase inhibitor diphenyliodonium chloride abrogated the PMA-dependent DC candidacidal capacity. Engagement of b-glucan receptor dectin-1 induced NADPH oxidase activation in DC that was depressed by mannose-binding receptor CD206 costimulation. Candida was internalized by DC through mannose-binding receptors, but not through dectin-1, thus explaining why Candida did not elicit NADPH oxidase activity. Our results indicate that NADPH oxidase is involved in DC Candida-killing activity, which is increased by IFN. However, Candida escapes the oxidative damage by inhibiting NADPH oxidase and by entering DC through receptors not involved in NADPH oxidase activation. IntroductionDendritic cells (DC) play an important role in the initiation of immune responses [1][2][3][4]. In peripheral tissues, immature DC capture antigens by specialized receptors, undergo maturation and migrate to lymphoid organs where they present antigens to naive T cells [1][2][3][4]. Moreover, DC produce cytotoxic molecules limiting pathogen replication [5][6][7][8].Recently, we reported that human monocyte-derived DC express NADPH oxidase [9], the enzyme of leukocytes responsible for ROS production, whose activation requires the association between cytosolic (p47phox, p67phox, p40phox, p21rac) and membrane (gp91phox, p22phox) components [10,11]. ROS produced by NADPH oxidase of leukocytes are involved in pathogen killing, as demonstrated by the recurrent infections affecting individuals with chronic granulomatous disease, an inherited disorder in which the enzyme is not functional [10,11], but are also recognized as signaling molecules [12]. We previously showed that NADPH oxidase is not involved in DC differentiation, LPS-induced maturation, cytokine production and induction of T cell proliferation, but is required for DC killing of intracellular bacteria [9].The present study was undertaken to elucidate in more detail the regulation of DC NADPH oxidase activity and the role of this enzyme in pathogen-killing ability of ResultsRegulation of NADPH oxidase activity by IFN-a and IFN-cWe previously reported that PMA-stimulated human monocyte-derived DC release superoxide anion, which was nearly completely produced via NADPH oxidase activation [9]. Here we show that immature DC treatment with IFN-a or IFN-c enhanced the PMA-induced NADPH oxidase activity (Fig.1A, B). A surface phenotype analysis by flow cytometry demonstrated that this effect was not consequent to changes of DC...

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Section: Discussionsupporting

confidence: 91%

supporting

confidence: 91%

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NADPH oxidase of human dendritic cells: Role in Candida albicans killing and regulation by interferons, dectin‐1 and CD206

et al. 2007

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“…IL-1␤ has been shown to be essential for host defenses against fungal pathogens (43), and several fungal pathogens have been shown to activate the NLRP3 inflammasome (44 -46). Our data suggest that cell wall chitin is unlikely to contribute greatly to the IL-1␤ release seen in response to fungal stimulation.…”

Section: Discussionmentioning

confidence: 99%

Chitosan but Not Chitin Activates the Inflammasome by a Mechanism Dependent upon Phagocytosis

Bueter

Lee

Rathinam

et al. 2011

Journal of Biological Chemistry

173

126

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Chitin is an abundant polysaccharide found in fungal cell walls, crustacean shells, and insect exoskeletons. The immunological properties of both chitin and its deacetylated derivative chitosan are of relevance because of frequent natural exposure and their use in medical applications. Depending on the preparation studied and the end point measured, these compounds have been reported to induce allergic responses, inflammatory responses, or no response at all. We prepared highly purified chitosan and chitin and examined the capacity of these glycans to stimulate murine macrophages to release the inflammasome-associated cytokine IL-1β. We found that although chitosan was a potent NLRP3 inflammasome activator, acetylation of the chitosan to chitin resulted in a near total loss of activity. The size of the chitosan particles played an important role, with small particles eliciting the greatest activity. An inverse relationship between size and stimulatory activity was demonstrated using chitosan passed through size exclusion filters as well as with chitosan-coated beads of defined size. Partial digestion of chitosan with pepsin resulted in a larger fraction of small phagocytosable particles and more potent inflammasome activity. Inhibition of phagocytosis with cytochalasin D abolished the IL-1β stimulatory activity of chitosan, offering an explanation for why the largest particles were nearly devoid of activity. Thus, the deacetylated polysaccharide chitosan potently activates the NLRP3 inflammasome in a phagocytosis-dependent manner. In contrast, chitin is relatively inert.

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“…Since Th1 and Th17 responses are thought to be beneficial for the host, the different responses of dendritic cells to yeast and hyphae may strongly influence the clinical course of infection. Morphology-dependent differences in cytokine production have also been demonstrated in macrophages [65] and monocytes [66].…”

Section: Epithelial Cellsmentioning

confidence: 99%

Candida albicansdimorphism as a therapeutic target

Jacobsen

Wilson

Wachtler

et al. 2012

Expert Review of Anti-infective Therapy

321

247

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Human dendritic cells are less potent at killing Candida albicans than both monocytes and macrophages

Cited by 56 publications

References 16 publications

NADPH oxidase of human dendritic cells: Role in Candida albicans killing and regulation by interferons, dectin‐1 and CD206

NADPH oxidase of human dendritic cells: Role in Candida albicans killing and regulation by interferons, dectin‐1 and CD206

Chitosan but Not Chitin Activates the Inflammasome by a Mechanism Dependent upon Phagocytosis

Candida albicansdimorphism as a therapeutic target

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