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  1. Article ; Online: Competitively disrupting the neutrophil-specific receptor-autoantigen CD177:proteinase 3 membrane complex reduces anti-PR3 antibody-induced neutrophil activation.

    Marino, Stephen F / Jerke, Uwe / Rolle, Susanne / Daumke, Oliver / Kettritz, Ralph

    The Journal of biological chemistry

    2022  Volume 298, Issue 3, Page(s) 101598

    Abstract: CD177 is a neutrophil-specific receptor presenting the proteinase 3 (PR3) autoantigen on the neutrophil surface. CD177 expression is restricted to a neutrophil subset, resulting in ... ...

    Abstract CD177 is a neutrophil-specific receptor presenting the proteinase 3 (PR3) autoantigen on the neutrophil surface. CD177 expression is restricted to a neutrophil subset, resulting in CD177
    MeSH term(s) Antibodies, Antineutrophil Cytoplasmic/immunology ; Antibodies, Monoclonal ; Autoantigens/immunology ; Cell Membrane/immunology ; GPI-Linked Proteins/immunology ; Granulomatosis with Polyangiitis/immunology ; Humans ; Isoantigens/metabolism ; Myeloblastin/metabolism ; Neutrophil Activation ; Neutrophils/immunology ; Receptors, Cell Surface/immunology ; Superoxides/immunology
    Chemical Substances Antibodies, Antineutrophil Cytoplasmic ; Antibodies, Monoclonal ; Autoantigens ; CD177 protein, human ; GPI-Linked Proteins ; Isoantigens ; Receptors, Cell Surface ; Superoxides (11062-77-4) ; Myeloblastin (EC 3.4.21.76)
    Language English
    Publishing date 2022-01-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.101598
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Characterization of the CD177 interaction with the ANCA antigen proteinase 3.

    Jerke, Uwe / Marino, Stephen F / Daumke, Oliver / Kettritz, Ralph

    Scientific reports

    2017  Volume 7, Page(s) 43328

    Abstract: Proteinase 3 is a serine protease found in neutrophil granules and on the extracellular neutrophil membrane (mPR3). mPR3 is a major antigen for anti-neutrophil cytoplasmic antibodies (PR3-ANCAs), autoantibodies causing fatal autoimmune diseases. In most ... ...

    Abstract Proteinase 3 is a serine protease found in neutrophil granules and on the extracellular neutrophil membrane (mPR3). mPR3 is a major antigen for anti-neutrophil cytoplasmic antibodies (PR3-ANCAs), autoantibodies causing fatal autoimmune diseases. In most individuals, a subpopulation of neutrophils also produce CD177, proposed to present additional PR3 on the surface, resulting in CD177
    MeSH term(s) Antibodies, Antineutrophil Cytoplasmic/biosynthesis ; Autoimmunity ; Cell Degranulation/immunology ; Endothelial Cells/immunology ; Endothelial Cells/pathology ; Epitopes/chemistry ; Epitopes/immunology ; GPI-Linked Proteins/genetics ; GPI-Linked Proteins/immunology ; Gene Expression Regulation ; HEK293 Cells ; Human Umbilical Vein Endothelial Cells/cytology ; Human Umbilical Vein Endothelial Cells/immunology ; Humans ; Isoantigens/genetics ; Isoantigens/immunology ; Models, Molecular ; Myeloblastin/genetics ; Myeloblastin/immunology ; Neutrophils/immunology ; Neutrophils/pathology ; Primary Cell Culture ; Protein Binding ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/immunology ; Signal Transduction ; Surface Plasmon Resonance
    Chemical Substances Antibodies, Antineutrophil Cytoplasmic ; CD177 protein, human ; Epitopes ; GPI-Linked Proteins ; Isoantigens ; Receptors, Cell Surface ; Myeloblastin (EC 3.4.21.76)
    Language English
    Publishing date 2017-02-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/srep43328
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Protective α1-antitrypsin effects in autoimmune vasculitis are compromised by methionine oxidation.

    Ebert, Maximilian / Jerke, Uwe / Eulenberg-Gustavus, Claudia / Kling, Lovis / Jenne, Dieter / Kirchner, Marieluise / Mertins, Philipp / Bieringer, Markus / Elitok, Saban / Eckardt, Kai-Uwe / Schreiber, Adrian / Salama, Alan D / Kettritz, Ralph

    The Journal of clinical investigation

    2022  Volume 132, Issue 23

    Abstract: BackgroundAntineutrophil cytoplasmic autoantibody-associated (ANCA-associated) vasculitidies (AAV) are life-threatening systemic autoimmune conditions. ANCAs directed against proteinase 3 (PR3) or myeloperoxidase (MPO) bind their cell surface-presented ... ...

    Abstract BackgroundAntineutrophil cytoplasmic autoantibody-associated (ANCA-associated) vasculitidies (AAV) are life-threatening systemic autoimmune conditions. ANCAs directed against proteinase 3 (PR3) or myeloperoxidase (MPO) bind their cell surface-presented antigen, activate neutrophils, and cause vasculitis. An imbalance between PR3 and its major inhibitor α1-antitrypsin (AAT) was proposed to underlie PR3- but not MPO-AAV. We measured AAT and PR3 in healthy individuals and patients with AAV and studied protective AAT effects pertaining to PR3- and MPO-ANCA.MethodsPlasma and blood neutrophils were assessed for PR3 and AAT. WT, mutant, and oxidation-resistant AAT species were produced to characterize AAT-PR3 interactions by flow cytometry, immunoblotting, fluorescence resonance energy transfer assays, and surface plasmon resonance measurements. Neutrophil activation was measured using the ferricytochrome C assay and AAT methionine-oxidation by Parallel Reaction Monitoring.ResultsWe found significantly increased PR3 and AAT pools in patients with both PR3- and MPO-AAV; however, only in PR3-AAV did the PR3 pool correlate with the ANCA titer, inflammatory response, and disease severity. Mechanistically, AAT prevented PR3 from binding to CD177, thereby reducing neutrophil surface antigen for ligation by PR3-ANCA. Active patients with PR3-AAV showed critical methionine-oxidation in plasma AAT that was recapitulated by ANCA-activated neutrophils. The protective PR3-related AAT effects were compromised by methionine-oxidation in the AAT reactive center loop but preserved when 2 critical methionines were substituted with valine and leucine.ConclusionPathogenic differences between PR3- and MPO-AAV are related to AAT regulation of membrane-PR3, attenuating neutrophil activation by PR3-ANCA rather than MPO-ANCA. Oxidation-resistant AAT could serve as adjunctive therapy in PR3-AAV.FUNDINGThis work was supported by KE 576/10-1 from the Deutsche Forschungsgemeinschaft, SCHR 771/8-1 from the Deutsche Forschungsgemeinschaft, grant 394046635 - SFB 1365 from the Deutsche Forschungsgemeinschaft, and ECRC grants.
    MeSH term(s) Humans ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ; Antibodies, Antineutrophil Cytoplasmic ; Giant Cell Arteritis ; Methionine/metabolism ; Mucocutaneous Lymph Node Syndrome ; Myeloblastin/genetics ; Neutrophil Activation ; Peroxidase/genetics ; Peroxidase/metabolism ; alpha 1-Antitrypsin/metabolism
    Chemical Substances Antibodies, Antineutrophil Cytoplasmic ; Methionine (AE28F7PNPL) ; Myeloblastin (EC 3.4.21.76) ; Peroxidase (EC 1.11.1.7) ; alpha 1-Antitrypsin
    Language English
    Publishing date 2022-12-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI160089
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ua VI Zs.184: Show issues Location:
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  4. Article ; Online: Targeting Cathepsin C in PR3-ANCA Vasculitis.

    Jerke, Uwe / Eulenberg-Gustavus, Claudia / Rousselle, Anthony / Nicklin, Paul / Kreideweiss, Stefan / Grundl, Marc A / Eickholz, Peter / Nickles, Katrin / Schreiber, Adrian / Korkmaz, Brice / Kettritz, Ralph

    Journal of the American Society of Nephrology : JASN

    2022  Volume 33, Issue 5, Page(s) 936–947

    Abstract: Background: The ANCA autoantigens proteinase 3 (PR3) and myeloperoxidase (MPO) are exclusively expressed by neutrophils and monocytes. ANCA-mediated activation of these cells is the key driver of the vascular injury process in ANCA-associated vasculitis ...

    Abstract Background: The ANCA autoantigens proteinase 3 (PR3) and myeloperoxidase (MPO) are exclusively expressed by neutrophils and monocytes. ANCA-mediated activation of these cells is the key driver of the vascular injury process in ANCA-associated vasculitis (AAV), and neutrophil serine proteases (NSPs) are disease mediators. Cathepsin C (CatC) from zymogens activates the proteolytic function of NSPs, including PR3. Lack of NSP zymogen activation results in neutrophils with strongly reduced NSP proteins.
    Methods: To explore AAV-relevant consequences of blocking NSP zymogen activation by CatC, we used myeloid cells from patients with Papillon-Lefèvre syndrome, a genetic deficiency of CatC, to assess NSPs and NSP-mediated endothelial cell injury. We also examined pharmacologic CatC inhibition in neutrophil-differentiated human hematopoietic stem cells, primary human umbilical vein cells, and primary glomerular microvascular endothelial cells.
    Results: Patients with Papillon-Lefèvre syndrome showed strongly reduced NSPs in neutrophils and monocytes. Neutrophils from these patients produced a negative PR3-ANCA test, presented less PR3 on the surface of viable and apoptotic cells, and caused significantly less damage in human umbilical vein cells. These findings were recapitulated in human stem cells, in which a highly specific CatC inhibitor, but not prednisolone, reduced NSPs without affecting neutrophil differentiation, reduced membrane PR3, and diminished neutrophil activation upon PR3-ANCA but not MPO-ANCA stimulation. Compared with healthy controls, neutrophils from patients with Papillon-Lefèvre syndrome transferred less proteolytically active NSPs to glomerular microvascular endothelial cells, the cell type targeted in ANCA-induced necrotizing crescentic glomerulonephritis. Finally, both genetic CatC deficiency and pharmacologic inhibition, but not prednisolone, reduced neutrophil-induced glomerular microvascular endothelial cell damage.
    Conclusions: These findings may offer encouragement for clinical studies of adjunctive CatC inhibitor in patients with PR3-AAV.
    MeSH term(s) Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ; Antibodies, Antineutrophil Cytoplasmic ; Cathepsin C/metabolism ; Endothelial Cells/metabolism ; Enzyme Precursors/metabolism ; Humans ; Myeloblastin/genetics ; Neutrophils/metabolism ; Papillon-Lefevre Disease/metabolism ; Peroxidase
    Chemical Substances Antibodies, Antineutrophil Cytoplasmic ; Enzyme Precursors ; Peroxidase (EC 1.11.1.7) ; Cathepsin C (EC 3.4.14.1) ; Myeloblastin (EC 3.4.21.76)
    Language English
    Publishing date 2022-03-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1085942-1
    ISSN 1533-3450 ; 1046-6673
    ISSN (online) 1533-3450
    ISSN 1046-6673
    DOI 10.1681/ASN.2021081112
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3344: Show issues Location:
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  5. Article ; Online: Lessons from a double-transgenic neutrophil approach to induce antiproteinase 3 antibody-mediated vasculitis in mice.

    Schreiber, Adrian / Eulenberg-Gustavus, Claudia / Bergmann, Astrid / Jerke, Uwe / Kettritz, Ralph

    Journal of leukocyte biology

    2016  Volume 100, Issue 6, Page(s) 1443–1452

    Abstract: ANCA to either PR3 or MPO are found in patients with necrotizing vasculitis and glomerulonephritis. ANCA binding to their target antigens on neutrophils and subsequent neutrophil activation are pivotal disease mechanisms that lead to vascular ... ...

    Abstract ANCA to either PR3 or MPO are found in patients with necrotizing vasculitis and glomerulonephritis. ANCA binding to their target antigens on neutrophils and subsequent neutrophil activation are pivotal disease mechanisms that lead to vascular inflammation and necrosis. ANCA interaction with PR3 is more complex than with MPO as the neutrophil-specific CD177 receptor is involved in PR3 surface expression and PR3-ANCA-induced neutrophil activation. Modeling human disease is important to clinical research. Highly successful mouse models of MPO-ANCA vasculitis exist; however, recapitulating PR3-ANCA vasculitis has not been successful. We generated double-transgenic (DT) mice that expressed human PR3 and CD177 under a myeloid-specific huMRP8 promoter in an attempt to model PR3-ANCA vasculitis. DT mice strongly expressed the human transgenes in and on murine neutrophils and bound murine and human anti-PR3 antibodies. Nevertheless, passive transfer of these antibodies into LPS-primed DT mice or immunization of C57BL/6 mice with human PR3 followed by irradiation and transplantation of DT bone marrow failed to induce glomerulonephritis. Further analyses revealed that anti-PR3 antibodies did not activate DT neutrophils as shown by superoxide generation. Moreover, we found that mice did not properly process human pro-PR3 into mature PR3 and, consequently, the signaling complex between PR3, CD177, and CD11b, which promotes neutrophil activation by anti-PR3 antibodies, failed to form. We conclude that important species differences in PR3 and CD177 exist between men and mice that prevented successful generation of a murine anti-PR3 antibody model.
    MeSH term(s) ATP-Binding Cassette Transporters/genetics ; Animals ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/genetics ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/immunology ; Antibodies, Antineutrophil Cytoplasmic/immunology ; CD11b Antigen/immunology ; Disease Models, Animal ; GPI-Linked Proteins/genetics ; Glomerulonephritis/etiology ; Glomerulonephritis/immunology ; Humans ; Immunization, Passive ; Immunoglobulin G/immunology ; Isoantigens/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myeloblastin/genetics ; Myeloblastin/immunology ; Myeloid Cells/immunology ; Myeloid Cells/metabolism ; Neutrophils/enzymology ; Promoter Regions, Genetic ; Radiation Chimera ; Receptors, Cell Surface/genetics ; Recombinant Proteins/immunology ; Respiratory Burst ; Species Specificity ; Specific Pathogen-Free Organisms ; Transgenes
    Chemical Substances ABCC11 protein, human ; Antibodies, Antineutrophil Cytoplasmic ; CD11b Antigen ; CD177 protein, human ; GPI-Linked Proteins ; Immunoglobulin G ; Isoantigens ; Receptors, Cell Surface ; Recombinant Proteins ; Myeloblastin (EC 3.4.21.76)
    Language English
    Publishing date 2016-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1189/jlb.5A0116-037R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Book ; Thesis: Ein neuer Urokinase Plasminogenaktivator-abhängiger Signalkomplex reguliert die Zellproliferation in vaskulären glatten Muskelzellen unter Beteiligung von Nucleolin und Casein Kinase 2

    Jerke, Uwe

    2000  

    Author's details von Uwe Jerke
    Keywords Nucleoline ; Urokinase ; Glatte Muskulatur ; Muskelzelle ; Proliferation ; Proteinkinase CK2
    Language German
    Size 1 Mikrofiche, Ill., graph. Darst
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Freie Univ., Diss.--Berlin, 2000
    Database Former special subject collection: coastal and deep sea fishing

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  7. Book ; Thesis: Ein neuer Urokinase Plasminogenaktivator-abhängiger Signalkomplex reguliert die Zellproliferation in vaskulären glatten Muskelzellen unter Beteiligung von Nucleolin und Casein Kinase 2

    Jerke, Uwe

    2000  

    Author's details von Uwe Jerke
    Keywords Nucleoline ; Urokinase ; Glatte Muskulatur ; Muskelzelle ; Proliferation ; Proteinkinase CK2
    Language German
    Size 1 Mikrofiche, Ill., graph. Darst
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Freie Univ., Diss.--Berlin, 2000
    Database Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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  8. Article ; Online: Neutrophil Gelatinase-Associated Lipocalin Protects from ANCA-Induced GN by Inhibiting T

    Schreiber, Adrian / Rousselle, Anthony / Klocke, Jan / Bachmann, Sebastian / Popovic, Suncica / Bontscho, Julia / Schmidt-Ott, Kai M / Siffrin, Volker / Jerke, Uwe / Ashraf, Muhammad Imtiaz / Panzer, Ulf / Kettritz, Ralph

    Journal of the American Society of Nephrology : JASN

    2020  Volume 31, Issue 7, Page(s) 1569–1584

    Abstract: Background: Neutrophil gelatinase-associated lipocalin (NGAL) is a diagnostic marker of intrinsic kidney injury produced by damaged renal cells and by neutrophils. ANCA-associated vasculitis features necrotizing crescentic GN (NCGN), and ANCA-activated ... ...

    Abstract Background: Neutrophil gelatinase-associated lipocalin (NGAL) is a diagnostic marker of intrinsic kidney injury produced by damaged renal cells and by neutrophils. ANCA-associated vasculitis features necrotizing crescentic GN (NCGN), and ANCA-activated neutrophils contribute to NCGN. Whether NGAL plays a mechanistic role in ANCA-associated vasculitis is unknown.
    Methods: We measured NGAL in patients with ANCA-associated vasculitis and mice with anti-myeloperoxidase (anti-MPO) antibody-induced NCGN. We compared kidney histology, neutrophil functions, T cell proliferation and polarization, renal infiltrating cells, and cytokines in wild-type and NGAL-deficient chimeric mice with anti-MPO antibody-induced NCGN. To assess the role of T
    Results: Mice and patients with active ANCA-associated vasculitis demonstrated strongly increased serum and urinary NGAL levels. ANCA-stimulated neutrophils released NGAL. Mice with NGAL-deficient bone marrow developed worsened MPO-ANCA-induced NCGN. Intrinsic neutrophil functions were similar in NGAL-deficient and wild-type neutrophils, whereas T cell immunity was increased in chimeric mice with NGAL-deficient neutrophils with more renal infiltrating T
    Conclusions: Our findings support that bone marrow-derived, presumably neutrophil, NGAL protects from ANCA-induced NCGN by downregulating T
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Animals ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/metabolism ; Antibodies, Antineutrophil Cytoplasmic ; CD28 Antigens/metabolism ; CD3 Complex/metabolism ; CD4-Positive T-Lymphocytes/physiology ; Cell Proliferation ; Chimera ; Disease Models, Animal ; Female ; Glomerulonephritis/immunology ; Glomerulonephritis/metabolism ; Glomerulonephritis/pathology ; Humans ; Immunity, Cellular ; Interleukin-17/genetics ; Kidney/pathology ; Lipocalin-2/genetics ; Lipocalin-2/metabolism ; Male ; Mice ; Middle Aged ; Neutrophils/metabolism ; Peroxidase/immunology ; Siderophores/metabolism ; Spleen/pathology ; Th17 Cells/immunology
    Chemical Substances Antibodies, Antineutrophil Cytoplasmic ; CD28 Antigens ; CD3 Complex ; Il17a protein, mouse ; Interleukin-17 ; LCN2 protein, human ; Lipocalin-2 ; Siderophores ; Lcn2 protein, mouse (126469-30-5) ; Peroxidase (EC 1.11.1.7)
    Language English
    Publishing date 2020-06-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1085942-1
    ISSN 1533-3450 ; 1046-6673
    ISSN (online) 1533-3450
    ISSN 1046-6673
    DOI 10.1681/ASN.2019090879
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3344: Show issues Location:
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  9. Article ; Online: Neutrophil serine proteases exert proteolytic activity on endothelial cells.

    Jerke, Uwe / Hernandez, Daniel Perez / Beaudette, Patrick / Korkmaz, Brice / Dittmar, Gunnar / Kettritz, Ralph

    Kidney international

    2015  Volume 88, Issue 4, Page(s) 764–775

    Abstract: Neutrophil serine proteases (NSPs) are released from activated neutrophils during inflammation. Here we studied the transfer of the three major NSPs, namely proteinase 3, human neutrophil elastase, and cathepsin G, from neutrophils to endothelial cells ... ...

    Abstract Neutrophil serine proteases (NSPs) are released from activated neutrophils during inflammation. Here we studied the transfer of the three major NSPs, namely proteinase 3, human neutrophil elastase, and cathepsin G, from neutrophils to endothelial cells and used an unbiased approach to identify novel endothelial NSP substrates. Enzymatically active NSPs were released from stimulated neutrophils and internalized by endothelial cells in a dose- and time-dependent manner as shown by immunoblotting, flow cytometry, and the Boc-Ala substrate assay. Using terminal-amine isotopic labeling of substrates in endothelial cells, we identified 121 peptides from 82 different proteins consisting of 36 substrates for proteinase 3, 30 for neutrophil elastase, and 28 for cathepsin G, respectively. We characterized the extended cleavage pattern and provide corresponding IceLogos. Gene ontology analysis showed significant cytoskeletal substrate enrichment and confirmed several cytoskeletal protein substrates by immunoblotting. Finally, ANCA-stimulated neutrophils released all three active NSPs into the supernatant. Supernatants increased endothelial albumin flux and disturbed the endothelial cell cytoskeletal architecture. Serine protease inhibition abrogated this effect. Longer exposure to NSPs reduced endothelial cell viability and increased apoptosis. Thus, we identified novel NSP substrates and suggest NSP inhibition as a therapeutic measure to inhibit neutrophil-mediated inflammatory vascular diseases.
    MeSH term(s) Actin Cytoskeleton/enzymology ; Albumins/metabolism ; Apoptosis ; Cathepsin G/metabolism ; Cell Line ; Cell Membrane Permeability ; Cell Survival ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects ; Endothelial Cells/enzymology ; Endothelial Cells/pathology ; Humans ; Leukocyte Elastase/metabolism ; Myeloblastin/metabolism ; Neutrophil Activation ; Neutrophils/enzymology ; Paracrine Communication ; Proteolysis ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Serine Endopeptidases/pharmacology ; Signal Transduction ; Substrate Specificity ; Time Factors
    Chemical Substances Albumins ; Serine Endopeptidases (EC 3.4.21.-) ; CTSG protein, human (EC 3.4.21.20) ; Cathepsin G (EC 3.4.21.20) ; Leukocyte Elastase (EC 3.4.21.37) ; Myeloblastin (EC 3.4.21.76)
    Language English
    Publishing date 2015-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120573-0
    ISSN 1523-1755 ; 0085-2538
    ISSN (online) 1523-1755
    ISSN 0085-2538
    DOI 10.1038/ki.2015.159
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: β2 integrin-mediated cell-cell contact transfers active myeloperoxidase from neutrophils to endothelial cells.

    Jerke, Uwe / Rolle, Susanne / Purfürst, Bettina / Luft, Friedrich C / Nauseef, William M / Kettritz, Ralph

    The Journal of biological chemistry

    2013  Volume 288, Issue 18, Page(s) 12910–12919

    Abstract: Atherosclerosis and vasculitis both feature inflammation mediated by neutrophil-endothelial cell (EC) contact. Neutrophil myeloperoxidase (MPO) can disrupt normal EC function, although the mechanism(s) by which MPO is transferred to ECs are unknown. We ... ...

    Abstract Atherosclerosis and vasculitis both feature inflammation mediated by neutrophil-endothelial cell (EC) contact. Neutrophil myeloperoxidase (MPO) can disrupt normal EC function, although the mechanism(s) by which MPO is transferred to ECs are unknown. We tested the hypothesis that close, β2 integrin-dependent neutrophil-EC contact mediates MPO transfer from neutrophils to ECs. We used sensitive MPO assays and flow cytometry to detect MPO in ECs and demonstrate that ECs acquired MPO when contacted by neutrophils directly but not when ECs and neutrophils were separated in Transwells. The transfer was dependent on neutrophil number, exposure time, and incubation temperature. Transfer occurred in several EC types, increased with endotoxin, was not accompanied by MPO release into the medium, and was not abrogated by inhibiting degranulation to secretagogues. Confocal microscopy showed MPO internalization by ECs with cytoplasmic and nuclear staining. Neutrophils and ECs formed intimate contact sites demonstrated by electron microscopy. Blocking CD11b or CD18 β2 integrin chains, or using neutrophils from CD11b gene-deleted mice, reduced MPO transfer. EC-acquired MPO was enzymatically active, as demonstrated by its ability to oxidize the fluorescent probe aminophenyl fluorescein in the presence of a hydrogen peroxide source. The data suggest an alternative to EC uptake of soluble MPO, namely the cell contact-dependent, β2 integrin-mediated transfer from neutrophils. The findings could be of therapeutic relevance in atherosclerosis and vasculitis.
    MeSH term(s) Animals ; Atherosclerosis/genetics ; Atherosclerosis/metabolism ; Atherosclerosis/pathology ; Atherosclerosis/therapy ; CD11b Antigen/genetics ; CD11b Antigen/metabolism ; CD18 Antigens/genetics ; CD18 Antigens/metabolism ; Cell Communication/drug effects ; Cell Communication/physiology ; Cell Degranulation ; Coculture Techniques ; Human Umbilical Vein Endothelial Cells/cytology ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Knockout ; Neutrophils/cytology ; Neutrophils/metabolism ; Peroxidase/genetics ; Peroxidase/metabolism ; Protein Transport/drug effects ; Protein Transport/physiology ; Vasculitis/genetics ; Vasculitis/metabolism ; Vasculitis/pathology ; Vasculitis/therapy
    Chemical Substances CD11b Antigen ; CD18 Antigens ; ITGAM protein, human ; Lipopolysaccharides ; Peroxidase (EC 1.11.1.7)
    Language English
    Publishing date 2013-03-26
    Publishing country United States
    Document type Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M112.434613
    Database MEDical Literature Analysis and Retrieval System OnLINE

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