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

•Grem1 decreases MIF-dependent monocyte migration and adhesion in vitro.•Intravenous administration of Grem1 inhibits leukocyte adhesion in vivo.•Grem1 reduces MIF-induced differentiation of monocytes into macrophages.•Grem1 inhibits the anti-apoptotic impact of MIF on monocytes.

BackgroundMonocyte 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 resultsWe 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.ConclusionsTherefore Gremlin-1 can modulate MIF dependent monocyte adhesion, migration, differentiation and survival.