Redox Regulation of Neutrophil Apoptosis

Watson, R.W.G.

doi:10.1089/152308602753625898

Cited by 40 publications

(38 citation statements)

References 63 publications

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“…As neutrophils can change their redox potential through their primary function of killing invading microorganisms, ROS generation as well as the presence of intracellular antioxidant molecules may interfere with the regulation of apoptosis in these cells. Although ROS and glutathione were shown to block caspase activity, both can inhibit, as well as trigger, apoptosis in human neutrophils, depending on the experimental conditions (41,42). These data indicate that the regulation of neutrophil survival most likely involves a delicate balance in the redox status of the cell rather than the prevalence of intracellular oxidants or antioxidants.…”

Section: Discussionmentioning

confidence: 99%

Heme Inhibits Human Neutrophil Apoptosis: Involvement of Phosphoinositide 3-Kinase, MAPK, and NF-κB

Arruda

Rossi

Freitas

et al. 2004

The Journal of Immunology

141

111

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High levels of free heme are found in pathological states of increased hemolysis, such as sickle cell disease, malaria, and ischemia reperfusion. The hemolytic events are often associated with an inflammatory response that usually turns into chronic inflammation. We recently reported that heme is a proinflammatory molecule, able to induce neutrophil migration, reactive oxygen species generation, and IL-8 expression. In this study, we show that heme (1–50 μM) delays human neutrophil spontaneous apoptosis in vitro. This effect requires heme oxygenase activity, and depends on reactive oxygen species production and on de novo protein synthesis. Inhibition of ERK and PI3K pathways abolished heme-protective effects upon human neutrophils, suggesting the involvement of the Ras/Raf/MAPK and PI3K pathway on this effect. Confirming the involvement of these pathways in the modulation of the antiapoptotic effect, heme induces Akt phosphorylation and ERK-2 nuclear translocation in neutrophils. Futhermore, inhibition of NF-κB translocation reversed heme antiapoptotic effect. NF-κB (p65 subunit) nuclear translocation and IκB degradation were also observed in heme-treated cells, indicating that free heme may regulate neutrophil life span modulating signaling pathways involved in cell survival. Our data suggest that free heme associated with hemolytic episodes might play an important role in the development of chronic inflammation by interfering with the longevity of neutrophils.

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Section: Discussionmentioning

confidence: 99%

Heme Inhibits Human Neutrophil Apoptosis: Involvement of Phosphoinositide 3-Kinase, MAPK, and NF-κB

Arruda

Rossi

Freitas

et al. 2004

The Journal of Immunology

141

111

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“…44,45 Consequently, redox signaling should be an important determinant of neutrophil apoptosis. 46 Although present knowledge of ER redox homeostasis and metabolism is limited, a logical explanation can be that defective G6PT transport alters the luminal redox status in the ER. In liver microsomes, both NADP ϩ -dependent dehydrogenases [47][48][49][50] and nicotinamide nucleotides 51 are present in the lumen; therefore, G6P can be metabolized not only by G6Pase but also by the intraluminal hexose-6-phosphate dehydrogenase.…”

Section: Discussionmentioning

confidence: 99%

“…In accordance with this assumption, caspase activation and apoptosis in HL-60 cells caused by oxidative challenges can be prevented by ascorbate and other antioxidants. 46,55,56 Very recent observations show that during the granulocytic differentiation, an ER remodeling occurs, affecting the size of the ER and the expression of its chaperones. 57 It is tempting to suppose that the defective G6PT hampers the remodeling program by causing maturation arrest and an early apoptosis of PMNs in GSD-1b patients.…”

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confidence: 99%

Inhibition of microsomal glucose-6-phosphate transport in human neutrophils results in apoptosis: a potential explanation for neutrophil dysfunction in glycogen storage disease type 1b

Leuzzi

Bánhegyi

Kardon

et al. 2003

Blood

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Mutations in the gene of the hepatic glucose-6-phosphate transporter cause glycogen storage disease type 1b. In this disease, the altered glucose homeostasis and liver functions are accompanied by an impairment of neutrophils/monocytes. However, neither the existence of a microsomal glucose-6-phosphate transport, nor the connection between its defect and cell dysfunction has been demonstrated in neutrophils/monocytes. In this study we have characterized the microsomal glucose-6-phosphate transport of human neutrophils and differentiated HL-60 cells. The transport of glucose-6-phosphate was sensitive to the chlorogenic acid derivative S3483, N-ethylmaleimide, and 4,4-diisothiocyanostilbene-2,2-disulfonic acid, known inhibitors of the hepatic microsomal glucose-6-phosphate transporter. A glucose-6-phosphate uptake was also present in microsomes from undifferentiated HL-60 and Jurkat cells, but it was insensitive to S3483. The treatment with S3484 of intact human neutrophils and differentiated HL-60 cells mimicked some leukocyte defects of glycogen storage disease type 1b patients (ie, the drug inhibited phorbol myristate acetate-induced superoxide anion production and reduced the size of endoplasmic reticulum Ca 2؉ stores). Importantly, the treatment with S3484 also resulted in apoptosis of human neutrophils and differentiated HL-60 cells, while undifferentiated HL-60 and Jurkat cells were unaffected by the drug. The proapoptotic effect of S3483 was prevented by the inhibition of nicotinamide adenine dinucleotide phosphate oxidase or by antioxidant treatment. These results suggest that microsomal glucose-6-phosphate transport has a role in the antioxidant protection of neutrophils, and that the genetic defect of the transporter leads to the impairment of cellular functions and apoptosis. IntroductionGlucose-6-phosphatase (G6Pase) catalyses the common terminal reaction of gluconeogenesis and glycogenolysis, hence it plays a major role in the maintenance of blood glucose homeostasis. 1,2 G6Pase is expressed mainly in the liver and in the kidney where it is associated with the endoplasmic reticulum (ER) and functions as a multicomponent system. 2 The system is composed of the enzyme protein with an intraluminal active site and transporters for the entry of substrate glucose-6-phosphate (G6P) and for the exit of the products, phosphate and glucose. 2,3 Both the enzyme and glucose-6-phosphate transporter (G6PT) are already known at the molecular level. 2,4,5 The deficiency of the G6Pase activity causes type 1 glycogen storage disease (GSD-1). 2,6 The genetic deficiency of the enzyme protein is termed GSD type 1a, 2,7 and mutations affecting the G6PT gene cause GSD type 1b. 2,5,[8][9][10][11][12][13] While the clinical feature in GSD-1a is dominated by metabolic alterations and hepatorenal symptoms, in GSD-1b polymorphonuclear neutrophils (PMNs) and monocytes are also affected. 2,7 Both neutropenia and functional defects of PMNs and monocytes have been observed in most GSD-1b patients, who are therefore affected by sev...

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“…In response to detection of microbial molecules, neutrophils produce a large quantity of microbicidal oxidative products in the so-called oxidative respiratory burst [32] . Respiratory bursts are also closely associated with neutrophil apoptosis [33] . MSCs inhibit neutrophil apoptosis, even under IL-8-mediated activation conditions, via MSC-derived IL-6 [34,35] .…”

Section: Interest In Immuno-modulatory Properties Of Mscsmentioning

confidence: 99%

Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy

Glenn¹

2014

WJSC

360

304

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Mesenchymal stem cells (MSCs) are a pleiotropic population of cells that are self-renewing and capable of differentiating into canonical cells of the mesenchyme, including adipocytes, chondrocytes, and osteocytes. They employ multi-faceted approaches to maintain bone marrow niche homeostasis and promote wound healing during injury. Biomedical research has long sought to exploit their pleiotropic properties as a basis for cell therapy for a variety of diseases and to facilitate hematopoietic stem cell establishment and stromal reconstruction in bone marrow transplantation. Early results demonstrated their usage as safe, and there was little host response to these cells. The discovery of their immunosuppressive functions ushered in a new interest in MSCs as a promising therapeutic tool to suppress inflammation and down-regulate pathogenic immune responses in graft-versus-host and autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. MSCs produce a large number of soluble and membrane-bound factors, some of which inhibit immune responses. However, the full range of MSC-mediated immune-modulation remains incompletely understood, as emerging reports also reveal that MSCs can adopt an immunogenic phenotype, stimulate immune cells, and yield seemingly contradictory results in experimental animal models of inflammatory disease. The present review describes the large body of literature that has been accumulated on the fascinating biology of MSCs and their complex effects on immune responses.

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Redox Regulation of Neutrophil Apoptosis

Cited by 40 publications

References 63 publications

Heme Inhibits Human Neutrophil Apoptosis: Involvement of Phosphoinositide 3-Kinase, MAPK, and NF-κB

Heme Inhibits Human Neutrophil Apoptosis: Involvement of Phosphoinositide 3-Kinase, MAPK, and NF-κB

Inhibition of microsomal glucose-6-phosphate transport in human neutrophils results in apoptosis: a potential explanation for neutrophil dysfunction in glycogen storage disease type 1b

Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy

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