Hydrogen Peroxide As an Immunological Transmitter Regulating Autoreactive T Cells

Holmdahl, Rikard; Sareila, Outi; Pizzolla, Angela; Winter, Susann; Hagert, Cecilia; Jaakkola, Noora; Kelkka, Tiina; Olsson, Lina; Wing, Kajsa; Bäckdahl, Liselotte

doi:10.1089/ars.2012.4734

Cited by 47 publications

(53 citation statements)

References 91 publications

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“…ROS can be toxic for neighboring cells as in the N-methyl-d-aspartate (NMDA)-mediated extracellular superoxide generation by neurons (140). However, it is tempting to hypothesize that paracrine regulation may occur as has been proposed for T-cell activation at the immunological synapse by NOX2-derived ROS (72).…”

Section: Physiological Role Of Nox In Cnsmentioning

confidence: 99%

“…Polymorphisms and mutations affecting the neutrophil cytosolic factor 1 (Ncf1) gene (coding for p47phox subunit) were shown to significantly increase susceptibility for autoimmune disease in rodents, including experimental autoimmune encephalomyelitis, a model of MS (9,76). This aspect of MS will not be discussed here, as the role of Ncf1 and NOX2-mediated oxidative burst in autoimmune disease by inhibiting T-cell activation has been extensively reviewed elsewhere (72,142). Indeed, once the disease is declared, a strong increase of NOX in MS lesions likely governs the oxidative damage of the myelin sheath.…”

Section: Fig 5 Activation Of Microglia Nox2mentioning

confidence: 99%

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New Insights onNOXEnzymes in the Central Nervous System

Nayernia

Jaquet

Krause

2014

Antioxidants & Redox Signaling

245

231

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Significance: There is increasing evidence that the generation of reactive oxygen species (ROS) in the central nervous system (CNS) involves the NOX family of nicotinamide adenine dinucleotide phosphate oxidases. Controlled ROS generation appears necessary for optimal functioning of the CNS through fine-tuning of redoxsensitive signaling pathways, while overshooting ROS generation will lead to oxidative stress and CNS disease. Recent Advances: NOX enzymes are not only restricted to microglia (i.e. brain phagocytes) but also expressed in neurons, astrocytes, and the neurovascular system. NOX enzymes are involved in CNS development, neural stem cell biology, and the function of mature neurons. While NOX2 appears to be a major source of pathological oxidative stress in the CNS, other NOX isoforms might also be of importance, for example, NOX4 in stroke. Globally speaking, there is now convincing evidence for a role of NOX enzymes in various neurodegenerative diseases, cerebrovascular diseases, and psychosis-related disorders. Critical Issues: The relative importance of specific ROS sources (e.g., NOX enzymes vs. mitochondria; NOX2 vs. NOX4) in different pathological processes needs further investigation. The absence of specific inhibitors limits the possibility to investigate specific therapeutic strategies. The uncritical use of non-specific inhibitors (e.g., apocynin, diphenylene iodonium) and poorly validated antibodies may lead to misleading conclusions. Future Directions: Physiological and pathophysiological studies with cell-type-specific knock-out mice will be necessary to delineate the precise functions of NOX enzymes and their implications in pathomechanisms. The development of CNS-permeant, specific NOX inhibitors will be necessary to advance toward therapeutic applications. Antioxid. Redox Signal. 20, 2815Signal. 20, -2837

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Section: Physiological Role Of Nox In Cnsmentioning

confidence: 99%

Section: Fig 5 Activation Of Microglia Nox2mentioning

confidence: 99%

New Insights onNOXEnzymes in the Central Nervous System

Nayernia

Jaquet

Krause

2014

Antioxidants & Redox Signaling

245

231

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“…ROS-deficient macrophages are hyperactive and cannot control chronic inflammation, which is dependent on an autocrine mechanism and regulation of interacting T-cell activities, leading to increased severity of arthritis and encephalomyelitis (reviewed in ref. 17). Here, we investigated the role of ROS in Ps-like skin and joint inflammation using B10Q.Ncf1 m1j/m1j mice that have a mutation in the Ncf1 gene (m1j) (the Ncf1 protein also denoted p47phox), and hence reduced ROS production (oxidative burst) (18).…”

Section: Ros Deficiency Exacerbated Mannan-induced Joint and Skin Infmentioning

confidence: 99%

Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

Khmaladze

Kelkka

Guérard

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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125

168

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Significance We identified a previously undescribed disease mechanism for psoriasis (Ps) and psoriasis arthritis (PsA)-like disease by developing a new mouse model having characteristic features similar to those of Ps and PsA in human patients. Mannan-induced activation of tissue macrophages triggers IL-17A secretion from γδ T cells, causing Ps-like inflammation. Such inflammation was significantly increased under a reduced oxidative environment. Increased frequency of monocytes/macrophages, depletion experiments, and the disease suppressor function of macrophage-derived reactive oxygen species clearly argue in favor of a role for monocytes/macrophages in this disease model, which is in accordance with the findings in patients with the psoriatic form of skin lesions and arthritis. This novel PsA model could be immensely useful to test new therapeutics for patients with Ps and PsA.

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“…In genetic studies comparing inflammationresistant E3 rats with Dark Agouti (DA) rats, which are predisposed to developing pristane-induced arthritis and other autoimmune conditions, the Pia4 region of the chromosome correlated with susceptibility to or severity of inflammatory diseases (101,253). Positional cloning identified NCF1 (encoding p47phox) as the gene that was responsible (204,313).…”

Section: Animal Model Association Of Autoimmune Disease With Compromimentioning

confidence: 99%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23,

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Hydrogen Peroxide As an Immunological Transmitter Regulating Autoreactive T Cells

Abstract: This may operate at different levels of T cell selection and activation: during negative selection in the thymus, priming of T cells in draining lymph nodes, and while interacting with macrophages in peripheral target tissues.

Cited by 47 publications

References 91 publications

New Insights onNOXEnzymes in the Central Nervous System

New Insights onNOXEnzymes in the Central Nervous System

Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

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