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| Verfasst von: | Haskamp, Stefan [VerfasserIn]  |
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| | Bruns, Heiko [VerfasserIn] |
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| | Hahn, Madelaine [VerfasserIn] |
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| | Hoffmann, Markus [VerfasserIn] |
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| | Gregor, Anne [VerfasserIn] |
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| | Löhr, Sabine [VerfasserIn] |
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| | Hahn, Jonas [VerfasserIn] |
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| | Schauer, Christine [VerfasserIn] |
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| | Ringer, Mark [VerfasserIn] |
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| | Flamann, Cindy [VerfasserIn] |
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| | Frey, Benjamin [VerfasserIn] |
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| | Lesner, Adam [VerfasserIn] |
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| | Thiel, Christian T. [VerfasserIn] |
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| | Ekici, Arif Bülent [VerfasserIn] |
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| | Hörsten, Stephan von [VerfasserIn] |
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| | Aßmann, Gunter [VerfasserIn] |
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| | Riepe, Claudia [VerfasserIn] |
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| | Euler, Maximilien [VerfasserIn] |
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| | Schäkel, Knut [VerfasserIn] |
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| | Philipp, Sandra [VerfasserIn] |
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| | Prinz, Jörg C. [VerfasserIn] |
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| | Mößner, Rotraut [VerfasserIn] |
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| | Kersting, Florina [VerfasserIn] |
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| | Sticherling, Michael [VerfasserIn] |
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| | Sefiani, Abdelaziz [VerfasserIn] |
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| | Lyahyai, Jaber [VerfasserIn] |
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| | Sondermann, Wiebke [VerfasserIn] |
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| | Oji, Vinzenz [VerfasserIn] |
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| | Schulz, Peter [VerfasserIn] |
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| | Wilsmann-Theis, Dagmar Irmgard [VerfasserIn] |
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| | Sticht, Heinrich [VerfasserIn] |
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| | Schett, Georg [VerfasserIn] |
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| | Reis, André [VerfasserIn] |
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| | Uebe, Steffen [VerfasserIn] |
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| | Frey, Silke [VerfasserIn] |
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| | Hüffmeier, Ulrike [VerfasserIn] |
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| Titel: | Myeloperoxidase modulates inflammation in generalized pustular psoriasis and additional rare pustular skin diseases |
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| Verf.angabe: | Stefan Haskamp, Heiko Bruns, Madelaine Hahn, Markus Hoffmann, Anne Gregor, Sabine Löhr, Jonas Hahn, Christine Schauer, Mark Ringer, Cindy Flamann, Benjamin Frey, Adam Lesner, Christian T. Thiel, Arif B. Ekici, Stephan von Hörsten, Gunter Aßmann, Claudia Riepe, Maximilien Euler, Knut Schäkel, Sandra Philipp, Jörg C. Prinz, Rotraut Mößner, Florina Kersting, Michael Sticherling, Abdelaziz Sefiani, Jaber Lyahyai, Wiebke Sondermann, Vinzenz Oji, Peter Schulz, Dagmar Wilsmann-Theis, Heinrich Sticht, Georg Schett, André Reis, Steffen Uebe, Silke Frey, Ulrike Hüffmeier |
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| E-Jahr: | 2020 |
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| Jahr: | 5 August 2020 |
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| Umfang: | 12 S. |
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| Fussnoten: | Gesehen am 18.02.2021 |
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| Titel Quelle: | Enthalten in: The American journal of human genetics |
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| Ort Quelle: | New York, NY [u.a.] : Cell Press, 1949 |
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| Jahr Quelle: | 2020 |
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| Band/Heft Quelle: | 107(2020), 3, Seite 527-538 |
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| ISSN Quelle: | 1537-6605 |
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| Abstract: | Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP’s pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases. |
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| DOI: | doi:10.1016/j.ajhg.2020.07.001 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext: https://doi.org/10.1016/j.ajhg.2020.07.001 |
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| | Volltext: https://www.sciencedirect.com/science/article/pii/S0002929720302317 |
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| | Volltext: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477008 |
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| | DOI: https://doi.org/10.1016/j.ajhg.2020.07.001 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| Sach-SW: | ACH |
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| | acrodermatitis continua suppurativa Hallopeau |
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| | activation of IL-36 precursors |
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| | acute generalized 4 exanthematous pustulosis |
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| | AGEP |
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| | efferocytosis |
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| | generalized pustular psoriasis |
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| | GPP |
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| | impaired NETosis |
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| | MPO deficiency |
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| | myeloperoxidase |
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| | oligogenic inheritance |
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| K10plus-PPN: | 1748653903 |
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| Verknüpfungen: | → Zeitschrift |
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Myeloperoxidase modulates inflammation in generalized pustular psoriasis and additional rare pustular skin diseases / Haskamp, Stefan [VerfasserIn]; 5 August 2020 (Online-Ressource)
