Macrophage Migration Inhibitory Factor (MIF) Limits Activation-Induced Apoptosis of Platelets via CXCR7-dependent Akt Signaling
Rationale: Macrophage migration inhibitory factor (MIF) is released upon 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 current 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 following CXCR4 ligation due to 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 anti-apoptotic effect of MIF was absent in Cxcr7-/- murine embryonic cells but pronounced in CXCR7 transfected MDCK cells. This pro-survival 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 following FeCl3-induced arterial injury in vivo, an effect mediated through CXCR7.
Conclusions: MIF interaction with CXCR7 modulates platelet survival and thrombotic potential both in vitro and in vivo, and thus could regulate thrombosis and inflammation.
- Received August 29, 2014.
- Revision received September 24, 2014.
- Accepted September 29, 2014.