Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases
Open accessAbstract
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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The MPO system has been involved in various skin pathologies, either serving as a causative factor or biomarker in inflammation, contact hypersensitivity and irritation, psoriasis, UV-damage, photoaging, and carcinogenesis.
“beyond a role in cutaneous innate immunity, the MPO system has also been involved in various skin pathologies, either serving as a causative factor or biomarker in inflammation, contact hypersensitivity and irritation, psoriasis, UV-damage, photoaging, and carcinogenesis (51–59).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [57]
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- Authors
- Haskamp, S., Bruns, H., Hahn, M., Hoffmann, M., Gregor, A., Löhr, S., Hahn, J., Schauer, C., Ringer, M., Flamann, C., Frey, B., Lesner, A., Thiel, C. T., Ekici, A. B., von Hörsten, S., Aßmann, G., Riepe, C., Euler, M., Schäkel, K., Philipp, S., Prinz, J. C., 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.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Universitätsklinikum Erlangen (DE)
- University of Gdańsk (PL)
- Saarland University (DE)
- University of Münster (DE)
- Heidelberg University (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Göttingen (DE)
- Mohammed V University (MA)
- University of Duisburg-Essen (DE)
- Corresponding author
- Hüffmeier, Ulrike
- ORCID
- Haskamp, Stefan
- Bruns, Heiko
- Hahn, Madelaine
- Hoffmann, Markus
- Gregor, Anne
- Löhr, Sabine
- Hahn, Jonas
- Frey, Benjamin
- Lesner, Adam
- Thiel, Christian T.
- Ekici, Arif B.
- Aßmann, Gunter
- Riepe, Claudia
- Euler, Maximilien
- Schäkel, Knut
- Philipp, Sandra
- Prinz, Jörg C.
- Mößner, Rotraut
- Sticherling, Michael
- Sefiani, Abdelaziz
- Lyahyai, Jaber
- Sondermann, Wiebke
- Oji, Vinzenz
- Schulz, Peter
- Sticht, Heinrich
- Schett, Georg
- Reis, André
- Uebe, Steffen
- Frey, Silke
- Hüffmeier, Ulrike
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 107
- Issue
- 3
- Pages
- 527-538
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC7477008
- OpenAlex
- W3047598936
- Cited by
- 84
- References
- 52
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 24 · 2023: 19 · 2022: 14 · 2021: 12 · 2020: 1 · 2013: 1
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- Funders
- Celgene
- Bundesministerium für Bildung und Forschung (01EC1407A, HU 2163/1-1)
- Deutsche Forschungsgemeinschaft (CRC1181)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Epidemiology › Autoimmune and Inflammatory Disorders
- Keywords
- generalized pustular psoriasis, myeloperoxidase, IL-36, IL36RN, pustular dermatosis, neutrophil extracellular traps, efferocytosis, proteolytic activity, neutrophil function, monocytes, age of onset, MPO inhibitors, inflammation resolution
- MeSH terms
- Adult, Animals, Female, Humans, Inflammation, Interleukin-1, Interleukins, Male, Mutation, Peroxidase, Neutrophils, Psoriasis, Skin, Skin Diseases, Cytokines, Rare Diseases, Mice, Extracellular Traps
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