Gremlin-1 inhibits macrophage migration inhibitory factor-dependent monocyte function and survival

• Published in: International journal of cardiology 2014-10, Vol.176 (3), p.923-929
• Main Authors: Müller, Iris I, Chatterjee, Madhumita, Schneider, Martina, Borst, Oliver, Seizer, Peter, Schönberger, Tanja, Vogel, Sebastian, Müller, Karin A.L, Geisler, Tobias, Lang, Florian, Langer, Harald, Gawaz, Meinrad
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Cardiology. Vascular system; Cardiovascular; Cell Line; Cell Movement - drug effects; Cell Movement - physiology; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Gremlin-1; Heart; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Signaling Peptides and Proteins - pharmacology; Macrophage Migration-Inhibitory Factors - antagonists & inhibitors; Macrophage Migration-Inhibitory Factors - physiology; Male; Medical sciences; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; MIF; Migration; Monocyte; Monocytes - drug effects; Monocytes - physiology
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2014.08.051

Abstract Background Monocyte migration and their differentiation into macrophages critically regulate vascular inflammation and atherogenesis and are governed by macrophage migration inhibitory factor (MIF). Gremlin-1 binds to MIF. Current experimental evidences present Gremlin-1 as a potential physiological agent that might counter-regulate the inflammatory attributes of MIF. Methods and results We found that Gremlin-1 inhibited MIF-dependent monocyte migration and adhesion to activated endothelial cells in flow chamber perfusion assay in vitro and to the injured carotid artery of WT and ApoE−/− mice in vivo as deciphered by intravital microscopy. Intravenous administration of Gremlin-1, but not of control protein, significantly reduced leukocyte recruitment towards the inflamed carotid artery of ApoE−/− mice. Besides, leukocytes from MIF−/− when administered into ApoE−/− mice showed lesser adhesion as compared to wild type. In the presence of Gremlin-1 however, adhesion of wild type, but not of MIF−/− leukocytes, to the carotid artery was significantly inhibited as compared to control. Gremlin-1 also inhibited the MIF-induced differentiation of monocytes into macrophages. Gremlin-1 substantially inhibited the anti-apoptotic impact of MIF on monocytes against BH3 mimetic ABT-737-induced apoptosis as verified by Annexin V-binding, caspase 3 activity, and mitochondrial depolarization. Conclusions Therefore Gremlin-1 can modulate MIF dependent monocyte adhesion, migration, differentiation and survival.