Cloning of the murine eosinophil peroxidase gene (mEPO): characterization of a conserved subgroup of mammalian hematopoietic peroxidases

Horton, Margaret A.; Larson, Kirsten A.; Lee, James J.; Lee, Nancy A.

doi:10.1002/jlb.60.2.285

Cited by 55 publications

(56 citation statements)

References 38 publications

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“…In rodents, eosinophil proteins with similar structure and activity have been identified (3)(4)(5)(6). In response to allergen provocation or parasitic infection, expanded eosinophil populations from the bone marrow are selectively recruited to affected tissues (1).…”

Section: Studies In Epomentioning

confidence: 99%

Post-translational Tyrosine Nitration of Eosinophil Granule Toxins Mediated by Eosinophil Peroxidase

Ulrich

Petre

Youhnovski

et al. 2008

Journal of Biological Chemistry

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Nitration of tyrosine residues has been observed during various acute and chronic inflammatory diseases. However, the mechanism of tyrosine nitration and the nature of the proteins that become tyrosine nitrated during inflammation remain unclear. Here we show that eosinophils but not other cell types including neutrophils contain nitrotyrosine-positive proteins in specific granules. Furthermore, we demonstrate that the human eosinophil toxins, eosinophil peroxidase (EPO), major basic protein, eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP), and the respective murine toxins, are post-translationally modified by nitration at tyrosine residues during cell maturation. High resolution affinity-mass spectrometry identified specific single nitration sites at Tyr 349 in EPO and Tyr 33 in both ECP and EDN. ECP and EDN crystal structures revealed and EPO structure modeling suggested that the nitrated tyrosine residues in the toxins are surface exposed. Studies in EPO ؊/؊ , gp91 phox؊/؊ , and NOS ؊/؊ mice revealed that tyrosine nitration of these toxins is mediated by EPO in the presence of hydrogen peroxide and minute amounts of NOx. Tyrosine nitration of eosinophil granule toxins occurs during maturation of eosinophils, independent of inflammation. These results provide evidence that post-translational tyrosine nitration is unique to eosinophils.Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), 3 major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules (1, 2). In rodents, eosinophil proteins with similar structure and activity have been identified (3-6). In response to allergen provocation or parasitic infection, expanded eosinophil populations from the bone marrow are selectively recruited to affected tissues (1). The release of cationic toxins from activated eosinophils by degranulation is regarded as a dominant effector function of these cells, mediating lysis of helminths and protozoae (7-10). The positive net charge conveys tight toxin binding to negatively charged cell surfaces where EPO causes oxidation of membrane components in the presence of hydrogen peroxide (H 2 O 2 ) (8). MBP increases membrane permeability and perturbation following insertion of apolar residues into the membrane (11), whereas ECP creates membrane channels (12). Both EDN and ECP exert ribonuclease activity (13). Due to their unspecific binding to membranes and their cytolytic activities, eosinophil granule proteins also cause host tissue damage during parasite infections and inflammatory disorders such as allergic asthma (14 -16). Despite advances in elucidating the mechanisms of action for the eosinophil granule proteins (1, 2), the cationic nature of these proteins (pI values Ͼ 10) would predict electrostatic repulsion and exclude interaction/cooperation of single granule proteins and among different granule proteins. Because sequen...

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Section: Studies In Epomentioning

confidence: 99%

Post-translational Tyrosine Nitration of Eosinophil Granule Toxins Mediated by Eosinophil Peroxidase

Ulrich

Petre

Youhnovski

et al. 2008

Journal of Biological Chemistry

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“…1,2 Three abundant groups of proteins exist among the numerous proteins stored in secondary granules (reviewed by Lee et al 3 ), including eosinophil major basic proteins (human and mouse: MBP-1 and MBP-2 4-7 ), eosinophil-associated ribonucleases (human: eosinophil-derived neurotoxin 8 and eosinophil cationic protein, 9 mouse: eosinophil-associated ribonucleases [Ear-1, -2, -6/7, -5/11 10,11 ]), and eosinophil peroxidase (human and mouse: EPX 12,13 ). The majority of the proteins stored in the secondary granules of eosinophils (by mass) is easily accounted for by MBP-1 and EPX, comprising ;50% and ;25%, respectively.…”

Section: Introductionmentioning

confidence: 99%

Expression of the secondary granule proteins major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX) is required for eosinophilopoiesis in mice

Doyle

Jacobsen

Ochkur

et al. 2013

Blood

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“…Eosinophils are recruited specifically to the developing liver granulomata, the site of active inflammation and tissue remodeling. Several eosinophil components implicated in debris scavenging and tissue remodeling activity include the eosinophil peroxidase, 8 the ribonucleases, 9 matrix metalloproteinases, 10 and the protease inhibitor, plasminogen activator inhibitor-2 (PAI-2). 11 Eosinophils may also play an important role in maintaining the Th2 response to infection via secretion of endogenous IL-4.…”

Section: Introductionmentioning

confidence: 99%

Schistosoma mansoni infection in eosinophil lineage–ablated mice

Swartz

Dyer

Cheever

et al. 2006

Blood

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We explore the controversial issue of the role of eosinophils in host defense against helminthic parasites using the established Schistosoma mansoni infection model in 2 novel mouse models of eosinophil lineage ablation (⌬dblGATA and TgPHIL). No eosinophils were detected in bone marrow of infected ⌬dblGATA or TgPHIL mice, despite the fact that serum IL-5 levels in these infected mice exceeded those in infected wild type by approximately 4-fold. Liver granulomata from infected ⌬dblGATA and TgPHIL mice were likewise depleted of eosinophils compared with those from their respective wild types. No eosinophil-dependent differences in granuloma number, size, or fibrosis were detected at weeks 8 or 12 of infection, and differential accumulation of mast cells was observed among the ⌬dblGATA mice only at week 12. Likewise, serum levels of liver transaminases, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) increased in all mice in response to S mansoni infection, with no eosinophil-dependent differences in hepatocellular damage observed. Finally, eosinophil ablation had no effect on worm burden or on egg deposition. Overall, our data indicate that eosinophil ablation has no impact on traditional measures of disease in the S mansoni infection model in mice. IntroductionThe role of eosinophils in host defense and disease remains controversial, and the debate continues as to whether these cells are active participants or simply bystanders in various pathophysiologic states. This is particularly so with respect to disease caused by helminthic parasites. While it would seem logical to assume that eosinophils should provide a measure of host defense against these important and endemic infections, as they are elicited in large numbers in response to helminth infection, and they degranulate on and cause damage to various forms of the parasitic helminthes in various in vitro settings, the results from numerous experiments performed in vivo have been equivocal. [1][2][3] The cytokine-mediated pathogenesis of the well-characterized mouse model of helminth infection, Schistosoma mansoni, has been described in great detail. [4][5][6][7] This infection includes a prominent Th2 phase, resulting in an increase in serum interleukin-5 (IL-5) in response to egg deposition in the portal circulation at weeks 6 to 8 after exposure to water-borne cercariae. Increased serum IL-5 results in massive bone marrow and blood eosinophilia. Eosinophils are recruited specifically to the developing liver granulomata, the site of active inflammation and tissue remodeling. Several eosinophil components implicated in debris scavenging and tissue remodeling activity include the eosinophil peroxidase, 8 the ribonucleases, 9 matrix metalloproteinases, 10 and the protease inhibitor, plasminogen activator inhibitor-2 (PAI-2). 11 Eosinophils may also play an important role in maintaining the Th2 response to infection via secretion of endogenous 13 Several groups began the exploration of the role of eosinophils in host defense against helmint...

show abstract

Cloning of the murine eosinophil peroxidase gene (mEPO): characterization of a conserved subgroup of mammalian hematopoietic peroxidases

Cited by 55 publications

References 38 publications

Post-translational Tyrosine Nitration of Eosinophil Granule Toxins Mediated by Eosinophil Peroxidase

Post-translational Tyrosine Nitration of Eosinophil Granule Toxins Mediated by Eosinophil Peroxidase

Expression of the secondary granule proteins major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX) is required for eosinophilopoiesis in mice

Schistosoma mansoni infection in eosinophil lineage–ablated mice

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