NOX2 Controls Phagosomal pH to Regulate Antigen Processing during Crosspresentation by Dendritic Cells

Savina, Ariel; Jancic, Carolina; Hugues, Stéphanie; Guermonprez, Pierre; Vargas, Pablo Agustín; Moura, Ivan C.; Lennon-Duménil, Ana-María; Seabra, Miguel C.; Raposo, Graça; Amigorena, Sébastian

doi:10.1016/j.cell.2006.05.035

Cited by 758 publications

(881 citation statements)

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“…These mechanisms could correspond to those observed by us in the absence of DC stimulation with PMA. Savina et al [50] suggest that in murine DC, NADPH oxidase is mainly involved in antigen processing. Our results indicate that NADPH oxidase also plays a role in Candida-killing activity of DC, in particular when ROS production is enhanced by IFN.…”

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confidence: 99%

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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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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“…Nevertheless, inhibition of Ag degradation is often related to increased Ag presentation, as demonstrated using Takahashi et al, 1989 protease inhibitors ( ), antigen resistant to degradation ( ) or modulation of intravacuolar pH ( Vidard et al, 1991Delamarre et al, 2006 ). Indeed, reduced intracellular proteolysis avoids the destruction of T cell epitopes, favoring the production of Savina et al, 2006 peptide-MHC classs II complexes. This is particularly important in cells such as macrophages which possess elevated degradation capacity due to their high protease content.…”

Section: Inhibitory Effect Of C3 Upon Tt Proteolysis In U937mentioning

confidence: 99%

A new role for complement C3: Regulation of antigen processing through an inhibitory activity

Villiers

Cretin

Lefebvre

et al. 2008

Molecular Immunology

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“…Several studies consistently showed that the phagosomal pH of macrophages decreases rapidly and equilibrates around pH 5.0 in 30 min (Nyberg et al, 1989;Lukacs et al, 1990Lukacs et al, , 1991Sturgill-Koszycki et al, 1994;Rybicka et al, 2010). To add to the variability, a phagosomal alkalization was reported in dendritic cells, the phagosomal pH reaching pH 7.6 within 1 hour of phagocytosis in these phagocytes (Savina et al, 2006). Limited levels of proteolysis within the phago-lysosomal system are critical for efficient antigen presentation by dendritic cells, and the alkalinization was proposed to prevent excessive proteolysis and antigen degradation.…”

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confidence: 95%

“…The alkalinization was strictly dependent on the activity of NOX2, and NOX2-deficient cells that did not produce superoxide failed to alkalinize (Savina et al, 2006;Mantegazza et al, 2008). Because the phagosomal alkalinization was linked to the ROS production, the alkalinization of dendritic cells phagosomes was attributed to the consumption of protons within phagosomes during the conversion of superoxide anions into hydrogen peroxide (Savina et al, 2006). However, as discussed above, superoxide production by NOX2 requires the movement of counter-ions to compensate for the charge of the electrons.…”

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confidence: 99%

“…Limited levels of proteolysis within the phago-lysosomal system are critical for efficient antigen presentation by dendritic cells, and the alkalinization was proposed to prevent excessive proteolysis and antigen degradation. The alkalinization was strictly dependent on the activity of NOX2, and NOX2-deficient cells that did not produce superoxide failed to alkalinize (Savina et al, 2006;Mantegazza et al, 2008). Because the phagosomal alkalinization was linked to the ROS production, the alkalinization of dendritic cells phagosomes was attributed to the consumption of protons within phagosomes during the conversion of superoxide anions into hydrogen peroxide (Savina et al, 2006).…”

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Do Hv1 proton channels regulate the ionic and redox homeostasis of phagosomes?

Chemaly

Demaurex

2012

Molecular and Cellular Endocrinology

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a b s t r a c tRecent work on animal models has revealed the important role played by the voltage-gated proton channel Hv1 during bacterial killing by innate immune cells. Studies from mice lacking Hv1 channels showed that Hv1 proton channels are required for high-level production of reactive oxygen species (ROS) by the NADPH oxidase of phagocytes (NOX2) in two ways. First, Hv1 channels maintain a physiological membrane potential during the respiratory burst of neutrophils by providing a compensating charge for the electrons transferred by NOX2 from NADPH to superoxide. Second, Hv1 channels maintain a physiological cytosolic pH by extruding the acid generated by the NOX2-dependent consumption of NADPH. The two mechanisms directly sustain the activity of the NOX2 enzyme and indirectly sustain other neutrophil functions by enhancing the driving force for the entry of calcium into cells, thereby boosting cellular calcium signals. The increased depolarization of Hv1-deficient neutrophils aborted calcium responses to chemoattractants and revealed adhesion and migration defects that were associated with an impaired depolymerization of the cortical actin cytoskeleton. Current research aims to transpose these findings to phagosomes, the phagocytic vacuoles where bacterial killing takes place. However, the mechanisms that control the phagosomal pH appear to vary greatly between phagocytes: phagosomes rapidly acidify in macrophages but remain neutral for several minutes in neutrophils following ingestion of solid particles, whereas in dendritic cells phagosomes alkalinize, a mechanism thought to promote antigen crosspresentation. In this review, we discuss how the knowledge gained on the role of Hv1 channels at the plasma membrane of neutrophils can be used to study the regulation of the phagosomal pH, ROS, membrane potential, and calcium fluxes in different phagocytic cells.

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NOX2 Controls Phagosomal pH to Regulate Antigen Processing during Crosspresentation by Dendritic Cells

Cited by 758 publications

References 42 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

A new role for complement C3: Regulation of antigen processing through an inhibitory activity

Do Hv1 proton channels regulate the ionic and redox homeostasis of phagosomes?

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