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.

Antwerp Surgical Training Anatomy and Research Centre University of Antwerp 2650 Edegem Belgium

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences 25242 Vestec Czech Republic

Department for Genomics and Immunoregulation LIMES Institute University of Bonn 53115 Bonn Germany

Department of Hepatology and Gastroenterology Charité Universitätsmedizin Berlin Campus Virchow Klinikum 13353 Berlin Germany

Deutsches Zentrum für Neurodegenerative Erkrankungen e 5 PRECISE Platform for Single Cell Genomics and Epigenomics at DZNE and the University of Bonn 53115 Bonn Germany

Division of Pneumology KU Leuven 3000 Leuven Belgium

Division of Pulmonary Allergy and Critical Care Medicine Department of Medicine University of Pittsburgh Pittsburgh PA 15261 USA

Division of Pulmonary Sciences and Critical Care Medicine University of Colorado Denver CO 80045 USA

Faculty of Science Technology and Medicine University of Luxembourg L 4365 Esch sur Alzette Luxembourg

Federal Center of Brain Research and Neurotechnologies Federal Medical Biological Agency Ostrovityanova1 bldg 10 117997 Moscow Russia

imed analytics 53121 Bonn Germany

Institute for Immunology Biomedical Center Faculty of Medicine Ludwig Maximilians Universität in Munich 82152 Planegg Martinsried Germany

Institute of Computational Biology Helmholtz Munich 85764 Munich Germany

Institute of Functional Epigenetics Helmholtz Munich 85764 Munich Germany

Institute of Lung Health and Immunity 85764 Munich Germany

Institute of Metabolism and Cell Death Helmholtz Munich 85764 Munich Germany

Koç University Research Center for Translational Medicine 34010 Istanbul Turkey

Laboratory for Translational Research in Obstructive Pulmonary Diseases Department of Respiratory Medicine Ghent University University Hospital Ghent 9000 Ghent Belgium

Max Delbrück Center for Molecular Medicine 13125 Berlin Germany

Pirogov Russian National Research Medical University Laboratory of Experimental Oncology Ostrovityanova 1 Moscow 117997 Russia

Proteomics of cellular signalling Luxembourg Institute of Health 1272 Strassen Luxembourg

Pulmonary Research Institute at LungenClinic Grosshansdorf Airway Research Center North 22927 Grosshansdorf Germany

Research Unit Molecular Immune Regulation Helmholtz Munich 81377 Munich Germany

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