title: Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment.
abstract: BACKGROUND
  Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl peptide receptor 2 (FPR2) is a chemoattractant receptor that recognizes proinflammatory and proresolving ligands. The contribution of FPR2 and its proresolving ligand annexin A1 to atherosclerotic lesion formation is largely undefined.
  
  
  OBJECTIVE
  Because of the ambivalence of FPR2 ligands, we here investigate the role of FPR2 and its resolving ligand annexin A1 in atherogenesis.
  
  
  RESULTS
  Deletion of FPR2 or its ligand annexin A1 enhances atherosclerotic lesion formation, arterial myeloid cell adhesion, and recruitment. Mechanistically, we identify annexin A1 as an endogenous inhibitor of integrin activation evoked by the chemokines CCL5, CCL2, and CXCL1. Specifically, the annexin A1 fragment Ac2-26 counteracts conformational activation and clustering of integrins on myeloid cells evoked by CCL5, CCL2, and CXCL1 through inhibiting activation of the small GTPase Rap1. In vivo administration of Ac2-26 largely diminishes arterial recruitment of myeloid cells in a FPR2-dependent fashion. This effect is also observed in the presence of selective antagonists to CCR5, CCR2, or CXCR2, whereas Ac2-26 was without effect when all 3 chemokine receptors were antagonized simultaneously. Finally, repeated treatment with Ac2-26 reduces atherosclerotic lesion sizes and lesional macrophage accumulation.
  
  
  CONCLUSIONS
  Instructing the annexin A1-FPR2 axis harbors a novel approach to target arterial leukocyte recruitment. With the ability of Ac2-26 to counteract integrin activation exerted by various chemokines, delivery of Ac2-26 may be superior in inhibition of arterial leukocyte recruitment when compared with blocking individual chemokine receptors.
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Maik
authors.initials: M
authors.lastname: Drechsler
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Renske
authors.initials: R
authors.lastname: de Jong
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Joana R
authors.initials: JR
authors.lastname: Viola
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Giovanna
authors.initials: G
authors.lastname: Leoni
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Jochen
authors.initials: J
authors.lastname: Grommes
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Döring
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany (M.D., R.d.J., J.R.V., G.L., J.G., C.W., Y.D., O.S.); Department of Pathology, Academic Medical Center (AMC), Amsterdam University, Amsterdam, The Netherlands (M.D., O.S.); Department of Anaesthesiology, University Münster, Münster, Germany (J.R., A.Z.); Max Planck Institute, Münster, Germany (J.R., A.Z.); Laboratory of Molecular Immunoregulation, NCI, Frederick, MD (J.M.W.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Aachen, Germany (J.G.); Medizinische Klinik und Poliklinik I, Klinikum Großhadern, LMU Munich, Munich, Germany (R.H., C.K.); and DZHK, Partner Site Munich Heart Alliance, Munich, Germany (R.H., C.K., C.W., O.S.). oliver.soehnlein@gmail.com.
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D001018:Aortic Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000502:physiology; D018946:Chemokine CCL5 / Q000502:physiology; D054360:Chemokine CXCL1 / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects; D004041:Dietary Fats / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors; D019713:Receptors, CCR5 / Q000502:physiology; D044042:Receptors, Formyl Peptide / Q000172:deficiency / Q000502:physiology; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors; D020827:rap1 GTP-Binding Proteins / Q000502:physiology
chemical_list: D017305:Annexin A1; D001057:Apolipoproteins E; C000592874:CCR5 protein, mouse; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D004041:Dietary Fats; D010455:Peptides; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D044042:Receptors, Formyl Peptide; D023063:Receptors, Interleukin-8B; C096153:annexin A1 peptide (2-26); C573274:annexin A1, mouse; C481578:formyl peptide receptor 2, mouse; D020827:rap1 GTP-Binding Proteins
keywords: annexin A1; atherosclerosis; chemokine; leukocytes