title: Macrophage migration inhibitory factor limits activation-induced apoptosis of platelets via CXCR7-dependent Akt signaling.
abstract: BACKGROUND
  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.
  
  
  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 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.
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Madhumita
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Britta
authors.initials: B
authors.lastname: Walker
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Anna
authors.initials: A
authors.lastname: Fotinos
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vogel
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Peter
authors.initials: P
authors.lastname: Seizer
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Mack
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Setareh
authors.initials: S
authors.lastname: Alampour-Rajabi
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Dominik
authors.initials: D
authors.lastname: Rath
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Tobias
authors.initials: T
authors.lastname: Geisler
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Harald F
authors.initials: HF
authors.lastname: Langer
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.).
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen (M.C., O.B., A.F., S.V., P.S., D.R., T.G., H.F.L., M.G.), Institute of Anatomy (A.M.), and Institute of Physiology (B.W., F.L.), Universität Tübingen, Tübingen, Germany; and Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Uniklinik RWTH Aachen, Aachen, Germany (S.A.-R., J.B.). meinrad.gawaz@med.uni-tuebingen.de.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D000818:Animals; D017209:Apoptosis; D001158:Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival; D004285:Dogs; D006801:Humans; D020935:MAP Kinase Signaling System; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D015539:Platelet Activation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D054387:Receptors, CXCR; D051025:bcl-Associated Death Protein; D051057:Proto-Oncogene Proteins c-akt; D013917:Thrombin
keywords: Akt; BAD; MIF; apoptosis; chemokine