Assessment of chlorination by human neutrophils

Foote, Christopher S.; Goyne, Thomas; Lehrer, Robert I.

doi:10.1038/301715a0

Cited by 285 publications

(156 citation statements)

References 13 publications

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“…The concentrations used in our experiments approach the concentrations of H 2 O 2 achieved by PMN in vitro (ϳ0.2 mM) (23). Moreover, a significant proportion of the H 2 O 2 made may be used to generate HOCl (24), and it is likely that the concentrations achieved within phagolysosomes are even higher.…”

Section: Discussionmentioning

confidence: 68%

Inflammatory Properties of IgG Modified by Oxygen Radicals and Peroxynitrite

Uesugi

Yoshida

Jasin

2000

The Journal of Immunology

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In inflammatory arthritis, there is evidence indicating that the affected tissues produce large amounts of oxygen-free radicals and NO. Herein, we examine the biologic effects of exposure of IgG to hypochlorous acid (HOCl) and peroxynitrite (ONOO). The concentrations of IgG modified by chlorination and nitrosation were measured in synovial fluids from inflammatory and noninflammatory arthritis. Human IgG was exposed to increasing concentrations of HOCl and ONOO, and the resulting products were tested for complement component binding; binding to FcγRI; activation of polymorphonuclear neutrophils; effect on the Ab-combining site of Abs; and in vivo inflammatory activity in a rabbit model of acute arthritis. Rheumatoid synovial fluids contained significantly greater concentrations of nitrosated and chlorinated IgG compared with ostearthritic specimens. In vitro exposure of human IgG to HOCl and ONOO resulted in a concentration-dependent decrease in C3 and C1q fixation. The decrease in Fc domain-dependent biologic functions was confirmed by competitive binding studies to the FcγRI of U937 cells. HOCl-treated IgG monomer was 10 times less effective in competing for binding compared with native IgG, and ONOO-treated IgG was 2.5 times less effective. The modified IgGs were also ineffective in inducing synthesis of H2O2 by human PMN. The Ag-binding domains of IgG also showed a concentration-dependent decrease in binding to Ag. The ability of the modified IgGs to induce acute inflammation in rabbit knees decreased 20-fold as gauged by the intensity of the inflammatory cell exudates. These studies clarify the modulating role of biological oxidants in inflammatory processes in which Ag-autoantibody reactions and immune complex pathogenesis may play an important role.

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Section: Discussionmentioning

confidence: 68%

Inflammatory Properties of IgG Modified by Oxygen Radicals and Peroxynitrite

Uesugi

Yoshida

Jasin

2000

The Journal of Immunology

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“…Previous demonstration that neutrophil proteins are chlorinated extensively supports this interpretation (16). In addition, a large fraction of the O 2 ⅐ Ϫ produced by neutrophils is converted into HOCl (13)(14)(15)(16)(17). For Ϸ4 M electrons introduced cumulatively into the phagosome over a few minutes (25) at a rate of 5-20 mM s Ϫ1 (26,27), Ϸ1 M Cl Ϫ is consumed to produce HOCl (17).…”

Section: Discussionmentioning

confidence: 91%

“…Roughly half of the O 2 ⅐ Ϫ generated by NADPH oxidase during the respiratory burst of phagocytosis is converted to HOCl by myeloperoxidase (MPO) (13)(14)(15)(16)(17). We therefore inhibited MPO by including 500 M ABAH (4-aminobenzoic acid hydrazide) in the medium (18).…”

Section: Hocl Diffusion From the Phagosome Contributes To Cytoplasmicmentioning

confidence: 99%

Voltage-gated proton channels maintain pH in human neutrophils during phagocytosis

Morgan

Capasso

Musset

et al. 2009

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

161

192

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Phagocytosis of microbial invaders represents a fundamental defense mechanism of the innate immune system. The subsequent killing of microbes is initiated by the respiratory burst, in which nicotinamide adenine dinucleotide phosphate (NADPH) oxidase generates vast amounts of superoxide anion, precursor to bactericidal reactive oxygen species. Cytoplasmic pH regulation is crucial because NADPH oxidase functions optimally at neutral pH, yet produces enormous quantities of protons. We monitored pH i in individual human neutrophils during phagocytosis of opsonized zymosan, using confocal imaging of the pH sensing dye SNARF-1, enhanced by shifted excitation and emission ratioing, or SEER. Despite long-standing dogma that Na ؉ /H ؉ antiport regulates pH during the phagocyte respiratory burst, we show here that voltage-gated proton channels are the first transporter to respond. During the initial phagocytotic event, pH i decreased sharply, and recovery required both Na ؉ /H ؉ antiport and proton current. Inhibiting myeloperoxidase attenuated the acidification, suggesting that diffusion of HOCl into the cytosol comprises a substantial acid load. Inhibiting proton channels with Zn 2؉ resulted in profound acidification to levels that inhibit NADPH oxidase. The pH changes accompanying phagocytosis in bone marrow phagocytes from HVCN1-deficient mice mirrored those in control mouse cells treated with Zn 2؉ . Both the rate and extent of acidification in HVCN1-deficient cells were twice larger than in control cells. In summary, acid extrusion by proton channels is essential to the production of reactive oxygen species during phagocytosis. innate immunity ͉ ion channels ͉ phagocyte ͉ respiratory burst ͉ SNARF W e have reinvestigated the regulation of cytoplasmic pH, pH i , in human neutrophils during phagocytosis. For 3 decades, pH i during the respiratory burst has been characterized as a small (0.05-0.1 unit) transient drop in pH i that is followed by larger (0.16-0.60 unit) prolonged alkalinization caused by Na ϩ /H ϩ antiport activity, whether the stimulus is fMLF (fMetLeuPhe, a chemotactic peptide), PMA (a PKC-activating phorbol ester), phospholipase C, or OPZ (opsonized zymosan) (1-7). In most studies, soluble stimuli were applied to populations of neutrophils. When phagocytosis was studied, the responses of many cells were averaged (5, 8). A powerful new imaging approach, confocal microscopy using the fluorescent pH indicator SNARF-1 enhanced by shifted excitation and emission ratioing (SEER) (9, 10) enabled us to examine the responses of individual cells with high spatial and temporal resolution. We report here that the behavior of individual human neutrophils during phagocytosis differs markedly from the prevailing view. The fundamental pH i response is triphasic: rapid and profound acidification followed by rapid but variably complete recovery, and after longer times, slow acidification that may reflect the onset of apoptosis. ResultsCells That Phagocytose Become Acidic. Human neutrophils were allowed to adhere to a g...

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“…Myeloperoxidase (MPO), a major phagocyte secreted protein, has been implicated in oxidative damage at sites of inflammation. It catalyzes the two-electron peroxidation of chloride to generate hypochlorous acid (HOCl) [2], a potent chlorinating oxidant, capable of chlorinating tyrosine into chlorotyrosine. Levels of chlorotyrosine are increased in atherosclerotic tissues [3] and the blood of in patients with inflammatory conditions including atherosclerosis [4,25,26].…”

Section: Introductionmentioning

confidence: 99%

Chlorotyrosine promotes human aortic smooth muscle cell migration through increasing superoxide anion production and ERK1/2 activation

Wang

Lin

et al. 2008

Atherosclerosis

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Chlorotyrosine is an oxidative product of hypochlorous acid and L-tyrosine, and is considered as a biomarker for oxidative stress and cardiovascular disease. However, it is not clear whether chlorotyrosine could directly contribute to vascular pathogenesis. In this study, we investigated the effect and potential mechanisms of chlorotyrosine on human aortic smooth muscle cell (AoSMC) migration. With Boyden chamber and wound healing assays, chlorotyrosine significantly increased AoSMC migration in a concentration-and time-dependent manner. In addition, chlorotyrosine significantly increased the expression of several key molecules related to cell migration including PDGF receptor-B (PDGFR-B), matrix metalloproteinases (MMP-1 and MMP-2) and integrins (α3, αV, and β3) in AoSMC at both mRNA and protein levels. Furthermore, chlorotyrosine also increased superoxide anion generation in AoSMC with the fluorescent dye dihydroethidium (DHE) staining. Activation of mitogen-activated protein kinases (MAPKs) was analyzed with Bio-Plex Luminex immunoassay and western blotting. Chlorotyrosine induced a transient phosphorylation of ERK1/2, but not JNK and p38 MAPKs. Antioxidants including selenomethionine (SeMet) and Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) as well as ERK1/2 inhibitor PD98059 effectively blocked chlorotyrosine-induced AoSMC migration. Thus, these findings demonstrate new biological functions of chlorotyrosine in human SMC migration, which may play a crucial role in the vascular lesion formation.

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Assessment of chlorination by human neutrophils

Cited by 285 publications

References 13 publications

Inflammatory Properties of IgG Modified by Oxygen Radicals and Peroxynitrite

Inflammatory Properties of IgG Modified by Oxygen Radicals and Peroxynitrite

Voltage-gated proton channels maintain pH in human neutrophils during phagocytosis

Chlorotyrosine promotes human aortic smooth muscle cell migration through increasing superoxide anion production and ERK1/2 activation

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