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

• DOI: 10.1038/s41467-022-28809-4
• Publication Date: 2022-03-14T11:03:08Z
• Authors: 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. Edel...; Marlene Sophia Ko...; Adrien Guillot; Kevin Bassler; Hannelore P. Van ...; Özgecan Kayalar; Nur Konyalilar; Tamara Kanashova; Sophie Rodius; Carolina Balleste...; Carlos M. Genes R...; 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; Ali Önder Yildirim
• Keywords: EXPRESSION; 0301 basic medicine; Protein-Arginine N-Methyltransferases; metabolism [Histones]; metabolism [Arginine]; Science; PRMT7 protein, human; KAPPA-B; PRMT2 protein, human; Animals; Arginine; Histones; Humans; Intracellular signaling peptides and proteins; Mice; Monocytes; Protein-arginine n-methyltransferases; Pulmonary disease; Chronic obstructive; Arginine; Multidisciplinary sciences; Article; Monocytes; Chronic obstructive; Histones; Mice; Pulmonary Disease, Chronic Obstructive; 03 medical and health sciences; INFLAMMATION; PRMT7 protein, mouse; SMOKE-INDUCED EMPHYSEMA; Medicine and Health Sciences; Animals; Humans; PHOSPHORYLATION; metabolism [Protein-Arginine N-Methyltransferases]; RAP1; Intracellular signaling peptides and proteins; Q; METHYLATION; Intracellular Signaling Peptides and Proteins; Biology and Life Sciences; Molecular Processes and Therapies [Topic 2]; 3. Good health; DIFFERENTIATION; Protein-arginine n-methyltransferases; CELLS; genetics [Pulmonary Disease, Chronic Obstructive]; Human medicine; ddc:500; Pulmonary disease; Technology Platforms; ELASTASE; metabolism [Monocytes]

AbstractExtravasation 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.