Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases

Haskamp S, Bruns H, Hahn M, Hoffmann M, Gregor A, Löhr S, Hahn J, Ringer M, Flamann C, Frey B, Lesner A, Thiel C, Ekici AB, von Hörsten S, Aßmann G, Riepe C, Euler M, Schäkel K, Philipp S, Prinz JC, Mößner R, Kersting F, Sticherling M, Sefiani A, Lyahyai J, Sondermann W, Oji V, Schulz P, Wilsmann-Theis D, Sticht H, Schett G, Reis A, Uebe S, Frey S, Hüffmeier U, Schauer C (2020)

Publication Type: Journal article

Publication year: 2020

Journal

American Journal of Human Genetics Elsevier (Cell Press)

Book Volume: 107

Pages Range: 527-538

Journal Issue: 3

DOI: 10.1016/j.ajhg.2020.07.001

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.

Authors with CRIS profile

Heiko Bruns Department of Medicine 5 – Haematology and Oncology Markus Hoffmann Medizinische Fakultät Anne Gregor Lehrstuhl für Humangenetik Sabine Löhr Lehrstuhl für Humangenetik Jonas Hahn Department of Medicine 3 – Rheumatology and Immunology Mark Ringer Department of Medicine 3 – Rheumatology and Immunology Cindy Flamann Department of Medicine 5 – Haematology and Oncology Benjamin Frey Department of Radiation Oncology Christian Thiel Medizinische Fakultät Arif Bülent Ekici Institute of Human Genetics Stephan von Hörsten Professur für Experimentelle Biomedizin Maximilien Euler Department of Medicine 3 – Rheumatology and Immunology Michael Sticherling Professur für Dermatologie Heinrich Sticht Professur für Bioinformatik Georg Schett Lehrstuhl für Innere Medizin III André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Steffen Uebe Institute of Human Genetics Silke Frey Department of Medicine 3 – Rheumatology and Immunology Ulrike Hüffmeier Lehrstuhl für Humangenetik Christine Schauer Department of Medicine 3 – Rheumatology and Immunology

Involved external institutions

University of Gdańsk / Uniwersytet Gdański PL Poland (PL) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE) Mohammed V University (UMVA) / جامعة محمد الخامس‎ MA Morocco (MA) Fachklinik Bad Bentheim DE Germany (DE) Georg-August-Universität Göttingen DE Germany (DE) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Humboldt-Universität zu Berlin DE Germany (DE) Universität Duisburg-Essen (UDE) DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE)

How to cite

APA:

Haskamp, S., Bruns, H., Hahn, M., Hoffmann, M., Gregor, A., Löhr, S.,... Schauer, C. (2020). Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases. American Journal of Human Genetics, 107(3), 527-538. https://dx.doi.org/10.1016/j.ajhg.2020.07.001

MLA:

Haskamp, Stefan, et al. "Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases." American Journal of Human Genetics 107.3 (2020): 527-538.

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