The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD

Gizem Günes Günsel, Thomas M. Conlon, Aicha Jeridi, Rinho Kim, Zeynep Ertüz, Niklas J. Lang, Meshal Ansari, Mariia Novikova, Dongsheng Jiang, Maximilian Strunz, Mariia Gaianova, Christine Hollauer, Christina Gabriel, Ilias Angelidis, Sebastian Doll, Jeanine C. Pestoni, Stephanie L. Edelmann, Marlene Sophia Kohlhepp, Adrien Guillot, Kevin Bassler, Hannelore P. Eeckhoutte, Özgecan Kayalar, Nur Konyalilar, Tamara Kanashova, Sophie Rodius, Carolina Ballester-López, Carlos M. Genes Robles, Natalia Smirnova, Markus Rehberg, Charu Agarwal, Ioanna Krikki, Benoit Piavaux, Stijn E. Verleden, Bart Vanaudenaerde, Melanie Königshoff, Gunnar Dittmar, Ken R. Bracke, Joachim L. Schultze, Henrik Watz, Oliver Eickelberg, Tobias Stoeger, Gerald Burgstaller, Frank Tacke, Vigo Heissmeyer, Yuval Rinkevich, Hasan Bayram, Herbert B. Schiller, Marcus Conrad, Robert Schneider and Ali Önder Yildirim ()
Additional contact information
Gizem Günes Günsel: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Thomas M. Conlon: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Aicha Jeridi: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Rinho Kim: Institute of Functional Epigenetics, Helmholtz Munich
Zeynep Ertüz: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Niklas J. Lang: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Meshal Ansari: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Mariia Novikova: Institute of Metabolism and Cell Death, Helmholtz Munich
Dongsheng Jiang: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Maximilian Strunz: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Mariia Gaianova: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Christine Hollauer: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Christina Gabriel: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Ilias Angelidis: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Sebastian Doll: Institute of Computational Biology, Helmholtz Munich
Jeanine C. Pestoni: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Stephanie L. Edelmann: Research Unit Molecular Immune Regulation, Helmholtz Munich
Marlene Sophia Kohlhepp: Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM)
Adrien Guillot: Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM)
Kevin Bassler: LIMES-Institute, University of Bonn
Hannelore P. Eeckhoutte: Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University, University Hospital Ghent
Özgecan Kayalar: Koç University Research Center for Translational Medicine (KUTTAM)
Nur Konyalilar: Koç University Research Center for Translational Medicine (KUTTAM)
Tamara Kanashova: Max-Delbrück Center for Molecular Medicine
Sophie Rodius: Proteomics of cellular signalling, Luxembourg Institute of Health
Carolina Ballester-López: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Carlos M. Genes Robles: Institute of Functional Epigenetics, Helmholtz Munich
Natalia Smirnova: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Markus Rehberg: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Charu Agarwal: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Ioanna Krikki: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Benoit Piavaux: Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences
Stijn E. Verleden: Division of Pneumology, KU Leuven
Bart Vanaudenaerde: Division of Pneumology, KU Leuven
Melanie Königshoff: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh
Gunnar Dittmar: Proteomics of cellular signalling, Luxembourg Institute of Health
Ken R. Bracke: Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University, University Hospital Ghent
Joachim L. Schultze: LIMES-Institute, University of Bonn
Henrik Watz: Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL)
Oliver Eickelberg: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh
Tobias Stoeger: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Gerald Burgstaller: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Frank Tacke: Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM)
Vigo Heissmeyer: Research Unit Molecular Immune Regulation, Helmholtz Munich
Yuval Rinkevich: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Hasan Bayram: Koç University Research Center for Translational Medicine (KUTTAM)
Herbert B. Schiller: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)
Marcus Conrad: Institute of Metabolism and Cell Death, Helmholtz Munich
Robert Schneider: Institute of Functional Epigenetics, Helmholtz Munich
Ali Önder Yildirim: Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL)

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract Extravasation of monocytes into tissue and to the site of injury is a fundamental immunological process, which requires rapid responses via post translational modifications (PTM) of proteins. Protein arginine methyltransferase 7 (PRMT7) is an epigenetic factor that has the capacity to mono-methylate histones on arginine residues. Here we show that in chronic obstructive pulmonary disease (COPD) patients, PRMT7 expression is elevated in the lung tissue and localized to the macrophages. In mouse models of COPD, lung fibrosis and skin injury, reduced expression of PRMT7 associates with decreased recruitment of monocytes to the site of injury and hence less severe symptoms. Mechanistically, activation of NF-κB/RelA in monocytes induces PRMT7 transcription and consequential mono-methylation of histones at the regulatory elements of RAP1A, which leads to increased transcription of this gene that is responsible for adhesion and migration of monocytes. Persistent monocyte-derived macrophage accumulation leads to ALOX5 over-expression and accumulation of its metabolite LTB4, which triggers expression of ACSL4 a ferroptosis promoting gene in lung epithelial cells. Conclusively, inhibition of arginine mono-methylation might offer targeted intervention in monocyte-driven inflammatory conditions that lead to extensive tissue damage if left untreated.

Date: 2022
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DOI: 10.1038/s41467-022-28809-4

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