Chemotactic Factor Inactivation by the Myeloperoxidase-Hydrogen Peroxide-Halide System

Clark, Robert A.; Klebanoff, Seymour J.

doi:10.1172/jci109557

Cited by 157 publications

(95 citation statements)

References 47 publications

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“…Consistently, neutrophil recruitment to sites of inflammation is dramatically elevated in the CGD mice (16). This hyperinflammatory phenotype is likely caused by dysfunctional kynurenine pathway of tryptophan catabolism (17) and suppression of ROS-induced deactivation of proinflammatory chemokines such as C5a, fMLP (18), LTB4 (19), and IL8 (20). At the sites of infection, the inability of CGD neutrophils to produce ROS in response to chemoattractant stimulation may contribute to the impaired bactericidal activity of these cells.…”

Section: Discussionmentioning

confidence: 90%

Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis

Hattori

Subramanian

Sakai

et al. 2010

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

137

102

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Neutrophil chemotaxis plays an essential role in innate immunity, but the underlying cellular mechanism is still not fully characterized. Here, using a small-molecule functional screening, we identified NADPH oxidase–dependent reactive oxygen species as key regulators of neutrophil chemotactic migration. Neutrophils with pharmacologically inhibited oxidase, or isolated from chronic granulomatous disease (CGD) patients and mice, formed more frequent multiple pseudopodia and lost their directionality as they migrated up a chemoattractant concentration gradient. Knocking down NADPH oxidase in differentiated neutrophil-like HL60 cells also led to defective chemotaxis. Consistent with the in vitro results, adoptively transferred CGD murine neutrophils showed impaired in vivo recruitment to sites of inflammation. Together, these results present a physiological role for reactive oxygen species in regulating neutrophil functions and shed light on the pathogenesis of CGD.

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Section: Discussionmentioning

confidence: 90%

Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis

Hattori

Subramanian

Sakai

et al. 2010

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

137

102

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“…This result may suggest that MPO has some protective effects on kidney disease. There are several reports demonstrating the role of MPO in antiinflammatory responses, such as inactivation of chemotactic proteins (22) and alterations of lymphocyte functions (23). Hypochlorous acid donor tetrachlorodecaoxide is currently reported as a monocyte modulator (24) and a post-transplantation immunosuppressant (25).…”

Section: Discussionmentioning

confidence: 99%

Functional Polymorphism of the Myeloperoxidase Gene in Hypertensive Nephrosclerosis Dialysis Patients

et al. 2007

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“…Microorganisms are phagocytosed normally, but persist within cells, which form a barrier to antibodies and extracellularly acting antibiotics. The resulting infectious foci stimulate granuloma formation, partly through release and persistence of chemoattractants, which require oxygen metabolites for their degradation (Clark & Klebanoff, 1979;Hamasaki et al, 1989). Chronic granulomatous inflammation may compromise vital organs and account for additional morbidity.…”

Section: Aetiology and Pathogenesis Of The Diseasementioning

confidence: 99%

“…Persistent inflammation in both CGD patients and mouse models of CGD can occur independently of infection (Morgenstern et al, 1997), so that inflammatory sites are frequently sterile. One possible explanation for the apparent failure to resolve inflammation, is the inability of CGD phagocytes to degrade chemotactic factors (Clark & Klebanoff, 1979;Hamasaki et al, 1989).…”

Section: Inflammationmentioning

confidence: 99%

Modern management of chronic granulomatous disease

2008

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SummaryChronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytic cells resulting in failure to kill a characteristic spectrum of bacteria and fungi and in defective degradation of inflammatory mediators with concomitant granuloma formation. Current prophylaxis with trimethoprim-sulfamethoxazole, itraconazole and in selected cases additional interferon gamma is efficient, but imperfect. A significant recent progress towards new antibiotic (e.g. linezolid) and antifungal (e.g. voriconazole and posaconazole) therapy will allow survival of most patients into adulthood. Adolescent and adult CGD is increasingly characterized by inflammatory complications, such as granulomatous lung and inflammatory bowel disease, requiring immunosupressive therapy. Allogeneic haematopoietic stem cell transplantation from a human leucocyte antigen identical donor is currently the only proven curative treatment for CGD and can be offered to the selected patients. Gene-replacement therapy for patients lacking a suitable stem cell donor is still experimental and faces major obstacles and risks. However, it may offer some transitory benefits and has helped in a few cases to overcome life-threatening infections.

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Chemotactic Factor Inactivation by the Myeloperoxidase-Hydrogen Peroxide-Halide System

Abstract: A B S T R A C T Polymorphonuclear leukocytes

Cited by 157 publications

References 47 publications

Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis

Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis

Functional Polymorphism of the Myeloperoxidase Gene in Hypertensive Nephrosclerosis Dialysis Patients

Modern management of chronic granulomatous disease

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