Myeloperoxidase Plays Critical Roles in Killing <i>Klebsiella pneumoniae</i> and Inactivating Neutrophil Elastase: Effects on Host Defense

Hirche, Tim O.; Gaut, Joseph P.; Heinecke, Jay W.; Belaaouaj, Abderrazzaq

doi:10.4049/jimmunol.174.3.1557

Cited by 108 publications

(84 citation statements)

References 48 publications

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“…In contrast, thiols react slowly with H 2 O 2 (K 2 Ͻ 5 ϫ 10 1 M Ϫ1 s Ϫ1 (43)), and peroxide did not oxidize TIQNDIMLLQLSR under our experimental conditions. When this peptide was oxidized with HOCl and then incubated with cathepsin G, it was converted to NDI(Mϩ16)LL, the same peptide that appears after HOCl oxidizes intact cathepsin G. Thus, alteration of the same residue in the peptide and the oxidized protein may confer susceptibility to cleavage by cathepsin G. Collectively, these observations indicate that oxidation of methionine residues can direct the regiospecific cleavage of peptides and proteins by cathepsin G. These findings may be of broader significance, because we recently showed that neutrophil elastase, another serine protease that is abundant in neutrophils, also degrades itself as it is oxidatively inactivated by HOCl (51).…”

Section: Discussionmentioning

confidence: 70%

Methionine Sulfoxide and Proteolytic Cleavage Contribute to the Inactivation of Cathepsin G by Hypochlorous Acid

Shao¹,

Belaaouaj

Verlinde

et al. 2005

Journal of Biological Chemistry

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Using myeloperoxidase and hydrogen peroxide, activated neutrophils produce high local concentrations of hypochlorous acid (HOCl). They also secrete cathepsin G, a serine protease implicated in cytokine release, receptor activation, and degradation of tissue proteins. Isolated cathepsin G was inactivated by HOCl but not by hydrogen peroxide in vitro. We found that activated neutrophils lost cathepsin G activity by a pathway requiring myeloperoxidase, suggesting that oxidants generated by myeloperoxidase might regulate cathepsin G activity in vivo. Tandem mass spectrometric analysis of oxidized cathepsin G revealed that loss of a peptide containing Asp 108 , which lies in the active site, associated quantitatively with loss of enzymatic activity. Catalytic domain peptides containing Asp 108 were lost from the oxidized protein in concert with the conversion of Met 110 to the sulfoxide. Release of this peptide was blocked by pretreating cathepsin G with phenylmethylsulfonyl fluoride, strongly implying that oxidation introduced proteolytic cleavage sites into cathepsin G. Model system studies demonstrated that methionine oxidation can direct the regiospecific proteolysis of peptides by cathepsin G. Thus, oxidation of Met 110 may contribute to cathepsin G inactivation by at least two distinct mechanisms. One involves direct oxidation of the thioether residue adjacent to the aspartic acid in the catalytic domain. The other involves the generation of new sites that are susceptible to proteolysis by cathepsin G. These observations raise the possibility that oxidants derived from neutrophils restrain pericellular proteolysis by inactivating cathepsin G. They also suggest that methionine oxidation could render cathepsin G susceptible to autolytic cleavage. Myeloperoxidase may thus play a previously unsuspected role in regulating tissue injury by serine proteases during inflammation.Neutrophils play a key role in host defense by migrating to sites of infection, where they phagocytose invading microorganisms (1). After a neutrophil encloses a microbe, the resulting phagosome fuses with granules containing microbicidal and digestive enzymes to form a phagolysosome. The azurophilic granules of neutrophils are rich in serine proteases, including cathepsin G and neutrophil elastase, which play critical roles in killing bacteria (2-4).Although such proteases are important for tissue homeostasis and host defense, an imbalance between proteases and their inhibitors is implicated in tissue damage during inflammation (5). It is therefore likely that plasma-derived inhibitors of cathepsin G, such as ␣ 1 -antichymotrypsin and ␣ 1 -antitrypsin, help limit proteolysis (6). However, traditional enzyme kinetics cannot fully explain the regulation of proteolysis by neutrophils. Thus, even in the presence of plasma-derived protease inhibitors, neutrophils produce evanescent "quantum bursts" of pericellular proteolytic activity (7). Cathepsin G could thus promote local proteolysis of a range of protein and peptide substrates, including cytoki...

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Section: Discussionmentioning

confidence: 70%

Methionine Sulfoxide and Proteolytic Cleavage Contribute to the Inactivation of Cathepsin G by Hypochlorous Acid

Shao¹,

Belaaouaj

Verlinde

et al. 2005

Journal of Biological Chemistry

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“…MPO has been shown to act as a physiologically relevant regulator of inflammatory response by oxidatively limiting tissue-degrading protease activity. 16,60 These reports raise the possibility that MPO might contribute to protection of the host from pathogens via diverse mechanisms associated with the activity of inflammatory mediators. Such a regulatory effect of MPO on inflammatory mediators might also help to explain our observations in Mpo Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

“…MPO has been closely involved in stimulating mitogen-activated protein kinase activity, cell growth, and protease activity, thereby influencing the immune responses and the progression of several inflammation-associated diseases. 10,[15][16][17][18][19] Until recently, phagocytic blood cells were thought to be the only cellular sources of MPO. However, recent studies 18,20,21 have shown that several cell types, including neuronal cells, express MPO under certain pathological conditions.…”

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confidence: 99%

Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Chang

Song

Jeon

et al. 2011

The American Journal of Pathology

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Rotenone exposure has emerged as an environmental risk factor for inflammation-associated neurodegenerative diseases. However, the underlying mechanisms responsible for the harmful effects of rotenone in the brain remain poorly understood. Herein, we report that myeloperoxidase (MPO) may have a potential regulatory role in rotenone-exposed brain-resident immune cells. We show that microglia, unlike neurons, do not undergo death; instead, they exhibit distinctive activated properties under rotenone-exposed conditions. Once activated by rotenone, microglia show increased production of reactive oxygen species, particularly HOCl. Notably, MPO, an HOClproducing enzyme that is undetectable under normal conditions, is significantly increased after exposure to rotenone. MPO-exposed glial cells also display characteristics of activated cells, producing proinflammatory cytokines and increasing their phagocytic activity. Interestingly, our studies with MPO inhibitors and MPO-knockout mice reveal that MPO deficiency potentiates, rather than inhibits, the rotenone-induced activated state of glia and promotes glial cell death. Furthermore, rotenone-triggered neuronal injury was more apparent in co-cultures with glial cells from Mpo ؊/؊ mice than in those from wildtype mice. Collectively, our data provide evidence that MPO has dual functionality under rotenone-exposed conditions, playing a critical regulatory role in modulating pathological and protective events in the brain.

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“…Bactericidal activity of neutrophils was assessed as described previously (37). 129.B6 F-1 mice received an i.p.…”

Section: Bactericidal Activity Of Neutrophils In Vivomentioning

confidence: 99%

Impaired Host Defense in Mice Lacking ONZIN

Ledford

Kovářová

Koller

2007

The Journal of Immunology

101

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ONZIN is a small, cysteine-rich peptide of unique structure that is conserved in all vertebrates examined to date. We show that ONZIN is expressed at high levels in epithelial cells of the intestinal tract, the lung, and in cells of the immune system including macrophages and granulocytes. Because this pattern of expression is suggestive of a role in innate immune function, we have generated mice lacking this protein and examined their ability to respond to challenge with infectious agents. Onzin−/− mice show a heightened innate immune response after induction of acute peritonitis with Klebsiella pneumoniae. This increased response is consistent with an increased bacterial burden in the Onzin−/− mice. Ex vivo studies show that, whereas phagocytosis is not altered in Onzin−/− neutrophils, phagocytes lacking this protein kill bacteria less effectively. This result identifies ONZIN as a novel class of intracellular protein required for optimal function of the neutrophils after uptake of bacteria.

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Myeloperoxidase Plays Critical Roles in Killing Klebsiella pneumoniae and Inactivating Neutrophil Elastase: Effects on Host Defense

Cited by 108 publications

References 48 publications

Methionine Sulfoxide and Proteolytic Cleavage Contribute to the Inactivation of Cathepsin G by Hypochlorous Acid

Methionine Sulfoxide and Proteolytic Cleavage Contribute to the Inactivation of Cathepsin G by Hypochlorous Acid

Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Impaired Host Defense in Mice Lacking ONZIN

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