Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease

Abstract Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent infections and deregulated inflammatory responses. CGD is caused by mutations in subunits of the NADPH oxidase, an enzyme that generates reactive oxygen species in phagocytes. To elucidate the contribution of the proinflammatory protease caspase-1 to aberrant inflammatory reactions in CGD, we analyzed cells isolated from patients with defects in the phagocyte oxidase subunits p22phox, p47phox or gp91phox. We report that mononuclear phagocytes from CGD patients activated caspase-1 and produced biologically active interleukin-1β (IL-1β) in response to danger signals. Notably, caspase-1 activation and IL-1β secretion from CGD monocytes was elevated in asymptomatic patients and strongly increased in patients with noninfectious inflammatory conditions. Treatment with IL-1 receptor antagonist reduced IL-1 production in monocytes ex vivo and during medical therapy. Our results identify phagocyte oxidase defective monocytes as a source of elevated IL-1 and provide a potential therapeutic option to ameliorate inflammatory conditions associated with CGD.

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Altered expression of neutrophil peripheral benzodiazepine receptor in X-linked chronic granulomatous disease

Blood ◽

10.1182/blood.v76.1.184.bloodjournal761184 ◽

1990 ◽

Vol 76 (1) ◽

pp. 184-188

Author(s):

F Zavala ◽

F Veber ◽

B Descamps-Latscha

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Host Defense ◽

Covalent Binding ◽

Benzodiazepine Receptor ◽

Mononuclear Phagocytes ◽

Human Neutrophils ◽

Granulomatous Disease ◽

Peripheral Benzodiazepine Receptor ◽

Cytochrome B558

This study was aimed at determining whether the peripheral benzodiazepine receptor (PBZDR), which is abundantly expressed on mononuclear phagocytes, is involved in host defense mechanisms depending on phagocyte membrane-associated NADPH-oxidase complex. Analysis by reversible and covalent binding of PBZDR expression on human neutrophils shows that it is modulated during NADPH-oxidase activation with phorbol 12-myristate 13-acetate. Based on a series of 17 patients with chronic granulomatous disease (CGD), results show that PBZDR expression is dramatically impaired in X-linked CGD, an inherited disorder due to a mutation on the gene coding for cytochrome b558 NADPH- oxidase component, whereas it is unaffected in autosomal recessive CGD where cytochrome b558 is normally expressed, suggesting a link between PBZDR and cytochrome b558 expressions. PBZDR can be assigned by covalent binding to an 18-Kd membrane protein. These results suggest that the neutrophil PBZDR, which can accommodate the widely prescribed anxiolytic drug Valium (diazepam), is involved in host defense against pathogens, a function that could be affected by neuroimmune interactions.

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Altered expression of neutrophil peripheral benzodiazepine receptor in X-linked chronic granulomatous disease

Blood ◽

10.1182/blood.v76.1.184.184 ◽

1990 ◽

Vol 76 (1) ◽

pp. 184-188 ◽

Cited By ~ 18

Author(s):

F Zavala ◽

F Veber ◽

B Descamps-Latscha

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Host Defense ◽

Covalent Binding ◽

Benzodiazepine Receptor ◽

Mononuclear Phagocytes ◽

Human Neutrophils ◽

Granulomatous Disease ◽

Peripheral Benzodiazepine Receptor ◽

Cytochrome B558

Abstract This study was aimed at determining whether the peripheral benzodiazepine receptor (PBZDR), which is abundantly expressed on mononuclear phagocytes, is involved in host defense mechanisms depending on phagocyte membrane-associated NADPH-oxidase complex. Analysis by reversible and covalent binding of PBZDR expression on human neutrophils shows that it is modulated during NADPH-oxidase activation with phorbol 12-myristate 13-acetate. Based on a series of 17 patients with chronic granulomatous disease (CGD), results show that PBZDR expression is dramatically impaired in X-linked CGD, an inherited disorder due to a mutation on the gene coding for cytochrome b558 NADPH- oxidase component, whereas it is unaffected in autosomal recessive CGD where cytochrome b558 is normally expressed, suggesting a link between PBZDR and cytochrome b558 expressions. PBZDR can be assigned by covalent binding to an 18-Kd membrane protein. These results suggest that the neutrophil PBZDR, which can accommodate the widely prescribed anxiolytic drug Valium (diazepam), is involved in host defense against pathogens, a function that could be affected by neuroimmune interactions.

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NADPH Oxidase 2 Derived Reactive Oxygen Species Promote CD8+ T cell Effector Function in Murine Model of Chronic Granulomatous Disease

10.26226/morressier.594a7d45d462b8028d8932ce ◽

2017 ◽

Author(s):

Jennifer Leiding

Keyword(s):

Reactive Oxygen Species ◽

T Cell ◽

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Murine Model ◽

Cd8 T Cell ◽

Oxygen Species ◽

Granulomatous Disease ◽

Cell Effector Function ◽

Cell Effector

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Staphylococcus aureus, phagocyte NADPH oxidase and chronic granulomatous disease

FEMS Microbiology Reviews ◽

10.1093/femsre/fuw042 ◽

2016 ◽

pp. fuw042 ◽

Cited By ~ 17

Author(s):

Helene Buvelot ◽

Klara M. Posfay-Barbe ◽

Patrick Linder ◽

Jacques Schrenzel ◽

Karl-Heinz Krause

Keyword(s):

Staphylococcus Aureus ◽

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Granulomatous Disease ◽

Phagocyte Nadph Oxidase

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Detection of gp91-phox precursor protein in B-cell lines from patients with X-linked chronic granulomatous disease as an indicator for mutations impairing cytochrome b558 biosynthesis

Biochemical Journal ◽

10.1042/bj3150571 ◽

1996 ◽

Vol 315 (2) ◽

pp. 571-575 ◽

Cited By ~ 15

Author(s):

Colin D. PORTER ◽

KURIBAYASHI KURIBAYASHI ◽

Mohamed H. PARKAR ◽

Dirk ROOS ◽

Christine KINNON

Keyword(s):

Nadph Oxidase ◽

B Cell ◽

Chronic Granulomatous Disease ◽

Cell Lines ◽

Binding Domain ◽

Granulomatous Disease ◽

Cytochrome B558 ◽

Stable Association ◽

P22 Phox ◽

Fad Binding

NADPH oxidase cytochrome b558 consists of two subunits, gp91-phox and p22-phox, defects of which result in chronic granulomatous disease (CGD). The nature of the interaction between these subunits has yet to be determined. Absence of p22-phox in autosomal CGD patient-derived B-cell lines results in detectable levels of an incompletely glycosylated gp91-phox precursor. We have detected this same precursor species in four cell lines from patients with the X-linked form of the disease due to mutations in gp91-phox. Such mutations should delineate regions of gp91-phox important for its biosynthesis, including stable association with p22-phox. One mutation mapped to the putative FAD-binding domain, one mapped to a potential haem-binding domain, and two involved the region encoded by exon 3.

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The p47phox mouse knock-out model of chronic granulomatous disease.

Journal of Experimental Medicine ◽

10.1084/jem.182.3.751 ◽

1995 ◽

Vol 182 (3) ◽

pp. 751-758 ◽

Cited By ~ 375

Author(s):

S H Jackson ◽

J I Gallin ◽

S M Holland

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Fungal Infections ◽

Critical Role ◽

Granulomatous Inflammation ◽

Mammalian Host ◽

Granulomatous Disease ◽

Knock Out ◽

Phagocyte Nadph Oxidase ◽

Life Threatening

Chronic granulomatous disease (CGD) is caused by a congenital defect in phagocyte reduced nicotinamide dinucleotide phosphate (NADPH) oxidase production of superoxide and related species. It is characterized by recurrent life-threatening bacterial and fungal infections and tissue granuloma formation. We have created a mouse model of CGD by targeted disruption of p47phox, one of the genes in which mutations cause human CGD. Identical to the case in human CGD, leukocytes from p47phox-/- mice produced no superoxide and killed staphylococci ineffectively. p47phox-/- mice developed lethal infections and granulomatous inflammation similar to those encountered in human CGD patients. This model mirrors human CGD and confirms a critical role for the phagocyte NADPH oxidase in mammalian host defense.

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Topics in Chronic Granulomatous Disease

PEDIATRICS ◽

10.1542/peds.88.1.183 ◽

1991 ◽

Vol 88 (1) ◽

pp. 183-185

Author(s):

SHIGENOBU UMEKI

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Host Defense ◽

Superoxide Anion ◽

Fungal Infections ◽

Regulatory Elements ◽

Granulomatous Disease ◽

Phagocytic Cells ◽

Oxidase System ◽

Membrane Bound

To the Editor.— Such phagocytic cells as neutrophils and macrophages are crucial elements in the host defense against bacterial [See table in the PDF file] and fungal infections. Microbicidal activity depends to a large extent on NADPH oxidase system, which can be activated by stimuli (bacteria, fungi) and which generates the superoxide anion and other highly reactive forms of reduced oxygen.1,2 The neutrophil NADPH oxidase system is composed functionally of membrane-bound catalytic components (which consist of at least two constituents, the low potential cytochrome b5583-5 and flavoprotein5) and soluble cytosolic components6,7 which participate as either catalytic or regulatory elements.

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