Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases
| Autor: | Jörg C. Prinz, Florina Kersting, Markus H. Hoffmann, Peter Schulz, Sabine Löhr, Jonas Hahn, Ulrike Hüffmeier, Christine Schauer, Gunter Aßmann, Anne Gregor, André Reis, Abdelaziz Sefiani, Arif B. Ekici, Sandra Philipp, Claudia Riepe, Wiebke Sondermann, Georg Schett, Madelaine Hahn, Knut Schäkel, Mark Ringer, Michael Sticherling, Silke Frey, Maximilien Euler, Christian Thiel, Jaber Lyahyai, Steffen Uebe, Heinrich Sticht, Stefan Haskamp, Dagmar Wilsmann-Theis, Cindy Flamann, Adam Lesner, Rotraut Mößner, Heiko Bruns, Vinzenz Oji, Stephan von Hörsten, Benjamin Frey |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Neutrophils Medizin Extracellular Traps Pathogenesis acute generalized 4 exanthematous pustulosis Mice 0302 clinical medicine Medicine oligogenic inheritance impaired NETosis Genetics (clinical) Skin efferocytosis biology AGEP 3. Good health myeloperoxidase 030220 oncology & carcinogenesis Myeloperoxidase Cytokines Female MPO deficiency generalized pustular psoriasis medicine.symptom acrodermatitis continua suppurativa Hallopeau Adult Proteases Phagocytosis Inflammation Skin Diseases Article 03 medical and health sciences Rare Diseases Genetics Animals Humans Psoriasis ACH Efferocytosis Peroxidase business.industry Interleukins Neutrophil extracellular traps activation of IL-36 precursors medicine.disease 030104 developmental biology Immunology Mutation Generalized pustular psoriasis biology.protein GPP business Interleukin-1 |
| Zdroj: | American Journal of Human Genetics |
| ISSN: | 1537-6605 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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