Reactive Oxygen Species Production in the Phagosome: Impact on Antigen Presentation in Dendritic Cells

Kotsias, Fiorella; Hoffmann, Eik; Amigorena, Sébastian; Savina, Ariel

doi:10.1089/ars.2012.4557

Cited by 111 publications

(110 citation statements)

References 146 publications

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“…For example, NOXdependent synthesis of (pathophysiological) H2O2 concentra- 90 Elevated levels of H2O2 derived from non-neutrophilic NOX isoforms in response to angiotensin II, endothelin-1, and aldosterone, among others, 91 are implicated in the development of systemic hypertension 92 and pulmonary hypertension 35 by inhibiting eNOS-dependent vasodilation. By contrast, physiological concentrations of H2O2 promote cell signaling processes, including normal cell proliferation, 93 migration, and survival, 94 as well as activation of eNOS.…”

Section: Hydrogen Peroxide-mediated Redox Regulation Of Enosmentioning

confidence: 99%

Subcellular Localization of Oxidants and Redox Modulation of Endothelial Nitric Oxide Synthase

Maron

Michel

2012

Circ J

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Reactive oxygen species (ROS) have long been viewed as deleterious chemicals that lead to oxidative stress. More recently, ROS, especially the stable ROS hydrogen peroxide (H2O2), have been shown to have roles in normal physiological responses in vascular cells. Endothelial nitric oxide synthase (eNOS) is dynamically targeted to plasmalemmal caveolae, and represents the principal enzymatic source of nitric oxide (NO • ) in the vascular wall. eNOS maintains normal vascular tone and inhibits the clinical expression of many cardiovascular diseases. Increases in oxidative stress are associated with eNOS dysfunction. In a paradigm shift in the conceptual framework linking redox biochemistry and vascular function, H2O2 has been established as a physiological mediator in signaling pathways, yet the intracellular sources of H2O2 and their regulation remain incompletely understood. The subcellular distributions of ROS and of ROS-modified proteins critically influence the redox-sensitive regulation of eNOS-dependent pathways. ROS localization in specific subcellular compartments can lead to selective oxidative modifications of eNOS and eNOS-associated proteins. Likewise, the dynamic targeting of eNOS and other signaling proteins influences their interactions with reactive nitrogen species and ROS that are also differentially distributed within the cell. Thus, the subcellular distribution both of eNOS and redox-active biomolecules serves as a critical basis for the control of the "redox switch" that influences NO• - and oxidant-regulated signaling pathways. Here we discuss the biochemical factors, cellular determinants, and molecular mechanisms that modulate redox-sensitive regulation of eNOS and NO tion of eNOS is dynamically regulated 9 and the enzyme is thus exposed to different concentrations of ROS depending upon where in the cell the protein is localized. Alterations in eNOS function due to changes in ROS levels may reflect either physiological or pathological responses in both normal cells and in vascular disease states. The relationship between impaired eNOS activity and the development of vascular dysfunction has been extensively studied: NO • is a potent vasodilator molecule that also attenuates platelet aggregation, vascular smooth muscle cell (VSMC) proliferation, and negative vascular remodeling. 10 Collectively, these properties contribute to the prevention of intermediate pathophenotypes of vascular disease, including cardiac and/or vascular hypertrophy, fibrosis, and atherosclerosis. In counterpoise to these deleterious effects of ROS, there also appears to be a key physiological role for H2O2 in eNOS regulation. 11 Elucidating the redoxdependent mechanisms involved in the physiological and pathophysiological regulation of eNOS by ROS will provide critical new insights into vascular disease states and may lead to the identification of novel treatment targets related to eNOS and eNOS-modulated vascular responses.

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Section: Hydrogen Peroxide-mediated Redox Regulation Of Enosmentioning

confidence: 99%

Subcellular Localization of Oxidants and Redox Modulation of Endothelial Nitric Oxide Synthase

Maron

Michel

2012

Circ J

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“…Although the individual chemistries within the phagosome are for the most part well characterized, how these chemistries affect one another and alter overall phagosome function has recently garnered great attention. Microenvironmental conditions that inhibit the activity of lysosomal proteases within the phagosomal lumen have undergone recent scrutiny (5,6). Of particular relevance to the current study, an oxidative microenvironment within the phagosome has been shown to inhibit lysosomal cysteine cathepsins within the phagosome of macrophages and dendritic cells (7,8).…”

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confidence: 93%

γ-Interferon-inducible Lysosomal Thiol Reductase (GILT) Maintains Phagosomal Proteolysis in Alternatively Activated Macrophages

Balce

Allan

McKenna

et al. 2014

Journal of Biological Chemistry

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Background: GILT is known to reduce disulfide bonds in endosomes, lysosomes, and phagosomes. Results: GILT, in addition to reducing disulfide bonds, maintains phagosomal proteolytic activity, particularly in alternatively activated macrophages. Conclusion: GILT maintains activity of cysteine proteases in phagosomes. Significance: These results reveal a novel role for GILT that may affect antigen processing and efficiency of hydrolysis of phagocytosed protein.

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“…Current models of obesitylinked adipose inflammation include leukocyte infiltration, increased levels of proinflammatory cytokines such as monocyte chemotactic protein-1, tumor necrosis factor-␣ (TNF␣), interleukin-6 (IL-6), and interleukin-1␤ (IL-1␤) and increased oxidative stress (14, 23). The dysfunction of the adipose tissue that occurs in the metabolic syndrome includes increased lipolysis in a fed state (20, 34) and alterations in adipokine secretion (8, 16), promoting the hypothesis that adipose inflammation underlies the metabolic syndrome and forms a platform for systemic dysfunction.In adipose tissue, macrophage infiltration leads to the production of reactive oxygen species (ROS) and increased oxidative stress in visceral depots (32,35,54). Production of ROS (and related reactive nitrogen species) results in oxidative damage to phospholipids, proteins, and DNA.…”

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confidence: 99%

Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics

Hahn

Kuzmicic

Burrill

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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DA. Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Am J Physiol Endocrinol Metab 306: E1033-E1045, 2014. First published March 4, 2014 doi:10.1152/ajpendo.00422.2013.-Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Macrophage infiltration of adipose tissue and the chronic low-grade production of inflammatory cytokines have been mechanistically linked to the development of insulin resistance, the forerunner of type 2 diabetes mellitus. In this study, we evaluated the chronic effects of TNF␣, IL-6, and IL-1␤ on adipocyte mitochondrial metabolism and morphology using the 3T3-L1 model cell system. TNF␣ treatment of cultured adipocytes led to significant changes in mitochondrial bioenergetics, including increased proton leak, decreased ⌬⌿m, increased basal respiration, and decreased ATP turnover. In contrast, although IL-6 and IL-1␤ decreased maximal respiratory capacity, they had no effect on ⌬⌿m and varied effects on ATP turnover, proton leak, or basal respiration. Only TNF␣ treatment of 3T3-L1 cells led to an increase in oxidative stress (as measured by superoxide anion production and protein carbonylation) and C16 ceramide synthesis. Treatment of 3T3-L1 adipocytes with cytokines led to decreased mRNA expression of key transcription factors and control proteins implicated in mitochondrial biogenesis, including PGC-1␣ and eNOS as well as deceased expression of COX IV and Cyt C. Whereas each cytokine led to effects on expression of mitochondrial markers, TNF␣ exclusively led to mitochondrial fragmentation and decreased the total level of OPA1 while increasing OPA1 cleavage, without expression of levels of mitofusin 2, DRP-1, or mitofilin being affected. In summary, these results indicate that inflammatory cytokines have unique and specialized effects on adipocyte metabolism, but each leads to decreased mitochondrial function and a reprogramming of fat cell biology. mitochondria; cytokine; fusion; adipocyte; respiration THE ADIPOSE ORGAN IS HIGHLY SPECIALIZED in storage and release of energy in times of nutrient excess and deficit, respectively (11,30). It also plays a vital role in communicating to the brain and other tissues as to the energy status of the entire organism and hence, can influence feeding behavior and energy utilization (9, 21, 52). Low-grade chronic inflammation of adipose tissue has been characterized as a hallmark of obesity and insulin resistance (14,17,50). Current models of obesitylinked adipose inflammation include leukocyte infiltration, increased levels of proinflammatory cytokines such as monocyte chemotactic protein-1, tumor necrosis factor-␣ (TNF␣), interleukin-6 (IL-6), and interleukin-1␤ (IL-1␤) and increased oxidative stress (14, 23). The dysfunction of the adipose tissue that occurs in the metabolic syndrome includes increased lipolysis in a fed state (20, 34) and alterations in adipokine secretion (8, 16), promoting the hypothesis that adipose ...

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Reactive Oxygen Species Production in the Phagosome: Impact on Antigen Presentation in Dendritic Cells

Cited by 111 publications

References 146 publications

Subcellular Localization of Oxidants and Redox Modulation of Endothelial Nitric Oxide Synthase

Subcellular Localization of Oxidants and Redox Modulation of Endothelial Nitric Oxide Synthase

γ-Interferon-inducible Lysosomal Thiol Reductase (GILT) Maintains Phagosomal Proteolysis in Alternatively Activated Macrophages

Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics

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