Haploinsufficiency of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 2 Is Sufficient to Accelerate Full‐Blown Lupus in NZM 2328 Mice

Jacob, Chaim O.; Yu, Ning; Yoo, Dae-Goon; Perez-Zapata, Lizet J.; Barbu, Emilia Alina; Kaplan, Mariana J.; Purmalek, Monica; Pingel, Jeanette T.; Idol, Rachel A.; Dinauer, Mary C.

doi:10.1002/art.40141

Cited by 49 publications

(33 citation statements)

References 46 publications

(73 reference statements)

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“…This point, which is punctuated by the current data, along with the lack of a role for neutrophils per se in driving lupus, heralds a juncture at which the field should seriously reevaluate whether the “NETs drive lupus” hypothesis remains valid and whether blocking NET formation or neutrophil function makes sense as a therapeutic strategy. In contrast, multiple studies have shown regulatory roles in various systems for CYBB, and to an extent PAD4 and MPO, such that disease is exacerbated in their absence [22, 23, 26, 27, 59]. We would thus posit that neutrophils and their effector mechanisms, such as NET generation, may have evolved to protect us from autoimmune diseases, rather than function as vectors to promote them.…”

Section: Discussionmentioning

confidence: 97%

Murine lupus is Neutrophil Elastase-independent in the MRL.Fas^lpr model

Gordon

Tilstra

Marinov

et al. 2019

Preprint

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AbstractLoss of tolerance to nuclear antigens and multisystem tissue destruction is a hallmark of systemic lupus erythematosus (SLE). Although the source of autoantigen in lupus remains elusive, a compelling hypothetical source is dead cell debris that drives autoimmune activation. Prior reports suggest that neutrophil extracellular traps (NETs) and their associated death pathway, NETosis, are sources of autoantigen in SLE. However, others and we have shown that inhibition of NETs by targeting the NADPH oxidase complex and peptidylarginine deiminase 4 (PADI4) did not ameliorate disease in spontaneous murine models of SLE. Furthermore, myeloperoxidase and PADI4 deletion did not inhibit induced lupus. Since NET formation may occur independently of any one mediator, to address this controversy, we genetically deleted an additional important mediator of NETs and neutrophil effector function, neutrophil elastase (ELANE), in the MRL.Faslpr model of SLE. ELANE deficiency, and by extension ELANE-dependent NETs, had no effect on SLE nephritis, dermatitis, anti-self response, or immune composition in MRL.Faslpr mice. Taken together with prior data from our group and others, these data further challenge the paradigm that NETs and neutrophils are pathogenic in SLE.

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Section: Discussionmentioning

confidence: 97%

Murine lupus is Neutrophil Elastase-independent in the MRL.Fas^lpr model

Gordon

Tilstra

Marinov

et al. 2019

Preprint

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“…АФК [7,17,26]. Синтез супероксид-радикала осуществляется экспрессированной на мембране клеток NADPH-оксидазой [14,21]. Известно, что хемилюминесцентная реакция люцигенина осуществляется только при взаимодействии с супероксид-радикалом [2,7].…”

Section: Discussionunclassified

Dependence of Neutrophil Respiratory Burst on Their Metabolic State in the Patients With Acute Destructive Pancreatitis of Different Severity

et al. 2019

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The aim of the study was to investigate a dependence of respiratory burst state in neutrophils on activities of their intracellular enzymes in patients with acute destructive pancreatitis (ADP) of different severity. The study included 50 patients with ADP of moderate (17 cases) and severe degree (33 cases). A group of 47 healthy people was examined as controls. The respiratory burst state was examined in neutrophilic granulocytes by means of chemiluminescence assays. A study of NAD(P)-dependent dehydrogenases activity in blood neutrophils was performed using bioluminescent analysis. We have revealed that a decrease in spontaneous and induced synthesis of superoxide radical by neutrophils was detected in ADP patients, independently of the disease severity. Kinetics of primary ROS synthesis was also impaired in patients with severe ADP. In patients with moderate disorder, the level of secondary ROS synthesis by neutrophils proved to be increased, whereas, in cases of severe disease, a disturbed kinetics of secondary ROS synthesis by neutrophils was detected at a resting state, showing increased synthetic level upon additional induction by zymosan. Metabolism of neutrophils in patients with ADP is characterized by activation of plastic processes (due to the products of the pentose phosphate cycle) and aerobic energy (increased substrate flow intensity in the cycle of tricarboxylic acids). However, NADPH neutrophilic pool in patients with moderate disorder could be additionally supported by enzymatic malic enzyme reactions and NADP-dependent glutamate dehydrogenase. Activation of peroxidation events in patients with severe ADP is revealed, which needs NADPH compensation. The state of energy processes in blood neutrophils in patients with ADP is characterized by lacking changes in glycolytic activity, and increased intensity of substrate flux along tricarboxylic acids cycle. Activity of aerobic processes in patients with moderate disease is maintained by the products of amino acid metabolism (via glutamate dehydrogenase), whereas, in severe ADP it may be provided by products of lipid catabolism. Using correlation analysis, a dependence of respiratory burst of neutrophils on the state of their metabolism was studied. We have found that intensity and kinetics of respiratory burst in the neutrophils of controls depends only on the activity of NADP-dependent dehydrogenases. The changes in cellular metabolic activity in the patients with moderate ADP led to disturbances of their regulatory effect upon the state of neutrophil respiratory burst. In patients with severe disorder, the degree a neutrophil respiratory burst is stimulated by reductive amination of α-ketoglutarate, being, however, inhibited by intracellular peroxidation processes.

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“…ROS deficiency also predisposes to autoimmune disorders. Oxidase null mice developed worse disease in models of collagen‐induced arthritis, mannan‐induced psoriasis and developed lupus‐like disease with glomerular‐nephritis . These data indicate that oxidants in fact are essential for suppressing excessive activation of host inflammatory responses triggered by endogenous and microbial stimulation.…”

Section: Nadph Oxidase Modulates Acute and Chronic Inflammatory Respomentioning

confidence: 93%

The roles of NADPH oxidase in modulating neutrophil effector responses

Zeng

Miralda

Armstrong

et al. 2019

Molecular Oral Microbiology

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Reactive oxygen species (ROS) collectively refer to a large group of highly reactive derivatives of oxygen generated as a consequence of metabolic processes or during host stress response. Although associated with oxidative damage, when produced at low regulated levels, oxidants are essential for redox modulation of cellular pathways, immune effector function, cell signaling and anti-microbial responses.The majority of ROS generated in a cell is by the activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases or NOX enzyme complexes. NOX enzyme family members NOX1, NOX2, NOX3, NOX4, NOX5 and the dual oxidase (DUOX) enzymes DUOX1, and DUOX2 are membrane associated hetero-oligomeric complexes that are dedicated to generation of ROS by using oxygen as its substrate. NOX enzymes are expressed in a cell specific or tissue specific manner and are rapidly activated in response to external stressors to generate large amounts of ROS. NOX2 or gp91 phox is the main catalytic subunit of the leukocyte NADPH oxidase complex. It is highly expressed in phagocytes (neutrophils, monocytes, macrophages, dendritic cells) and at much lower levels in lymphocytes, endothelial cells and colonic epithelial cells. 1,2 NOX2 derived oxidants modulate multiple cellular processes independent of their anti-microbial function. For instance, NADPH oxidase activation is essential for antigen presentation in B cells 3 , T cell receptor stimulation 4

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Haploinsufficiency of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 2 Is Sufficient to Accelerate Full‐Blown Lupus in NZM 2328 Mice

Cited by 49 publications

References 46 publications

Murine lupus is Neutrophil Elastase-independent in the MRL.Fas^lpr model

Murine lupus is Neutrophil Elastase-independent in the MRL.Fas^lpr model

Dependence of Neutrophil Respiratory Burst on Their Metabolic State in the Patients With Acute Destructive Pancreatitis of Different Severity

The roles of NADPH oxidase in modulating neutrophil effector responses

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Haploinsufficiency of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 2 Is Sufficient to Accelerate Full‐Blown Lupus in NZM 2328 Mice

Cited by 49 publications

References 46 publications

Murine lupus is Neutrophil Elastase-independent in the MRL.Faslpr model

Murine lupus is Neutrophil Elastase-independent in the MRL.Faslpr model

Dependence of Neutrophil Respiratory Burst on Their Metabolic State in the Patients With Acute Destructive Pancreatitis of Different Severity

The roles of NADPH oxidase in modulating neutrophil effector responses

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Murine lupus is Neutrophil Elastase-independent in the MRL.Fas^lpr model

Murine lupus is Neutrophil Elastase-independent in the MRL.Fas^lpr model