Macrophage Migration Inhibitory Factor Limits Activation-Induced Apoptosis of Platelets via CXCR7-Dependent Akt Signaling

Abstract

Rationale: Macrophage migration inhibitory factor (MIF) is released on platelet activation. Circulating MIF could potentially regulate platelets and thereby platelet-mediated inflammatory and regenerative mechanisms. However, the effect of MIF on platelets is unknown. Objective: The present study evaluated MIF in regulating platelet survival and thrombotic potential. Methods and Results: MIF interacted with CXCR4-CXCR7 on platelets, defining CXCR7 as a hitherto unrecognized receptor for MIF on platelets. MIF internalized CXCR4, but unlike CXCL12 (SDF-1α), it did not phosphorylate Erk1/2 after CXCR4 ligation because of the lack of CD74 and failed in subsequent CXCR7 externalization. MIF did not alter the activation status of platelets. However, MIF rescued platelets from activation and BH3 mimetic ABT-737–induced apoptosis in vitro via CXCR7 and enhanced circulating platelet survival when administered in vivo. The antiapoptotic effect of MIF was absent in Cxcr7 −/− murine embryonic cells but pronounced in CXCR7-transfected Madin–Darby canine kidney cells. This prosurvival effect was attributed to the MIF–CXCR7–initiated PI3K-Akt pathway. MIF induced CXCR7-Akt–dependent phosphorylation of BCL-2 antagonist of cell death (BAD) both in vitro and in vivo. Consequentially, MIF failed to rescue Akt −/− platelets from thrombin-induced apoptosis when challenged ex vivo, also in prolonging platelet survival and in inducing BAD phosphorylation among Akt −/− mice in vivo. MIF reduced thrombus formation under arterial flow conditions in vitro and retarded thrombotic occlusion after FeCl 3 -induced arterial injury in vivo, an effect mediated through CXCR7. Conclusion: MIF interaction with CXCR7 modulates platelet survival and thrombotic potential both in vitro and in vivo and thus could regulate thrombosis and inflammation.

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

“…Therefore, MIF fails in subsequent CXCR7 surface translocation. This suggests a ligand-specific (MIF vs SDF-1α) effect on CXCR4-triggered signalling in platelets, possibly to govern distinct cellular functions (32). Increased surface expression of CXCR7 among patients with acute coronary syndrome (ACS) correlates with the expression of its ligand SDF-1α and recovery of the ventricular function (30).…”

“…Platelets harbour three femtogram MIF/cell and -owing to their abundance in circulation -might have a profound influence in modulating vascular inflammation by instigating monocyte migration (34) or potentially contributing to elevated plasma MIF levels in patients with acute myocardial infarction (MI) (35). MIF rescues platelets from undergoing apoptosis through CXCR7 like SDF-1α and CXCL11 and sustains platelet life span in circulation as well (32). Since the anti-apoptotic effect of the MIF/CXCR7 interaction involves an attenuation of prothrombotic phosphatidylserine exposure on the platelet surface, MIF counter-regulates thrombus formation, both in vitro and following arterial injury in vivo through CXCR7 involvement without altering integrin activation (Procaspase Activating Compound-1 [PAC-1] binding) (32).…”

“…MIF rescues platelets from undergoing apoptosis through CXCR7 like SDF-1α and CXCL11 and sustains platelet life span in circulation as well (32). Since the anti-apoptotic effect of the MIF/CXCR7 interaction involves an attenuation of prothrombotic phosphatidylserine exposure on the platelet surface, MIF counter-regulates thrombus formation, both in vitro and following arterial injury in vivo through CXCR7 involvement without altering integrin activation (Procaspase Activating Compound-1 [PAC-1] binding) (32). This could bear promising clinical relevance in patients undergoing anti-platelet therapy against cardiovascular syndromes and cerebral ischaemia.…”

“…They show sustained survival in blood circulation, which may profoundly influence the duration and resolution of inflammatory processes, e. g. onset and progression of atherosclerosis, plaque stability and CAD. (32). B) Bar diagram of the flow cytometry data representing release of MIF, SDF-1α and CXCL11 denoted by their relative surface expression with respect to resting platelets, upon activation with ADP (100 µM).…”

“…Data presented as mean±S. E.M of five independent experiments (32). C) Schematic representation of the surface receptors for MIF, SDF-1α and CXCL11 on platelet surface.…”