title: Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment.
abstract: Therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis has been disappointing in clinical studies. Reasons for such failures include the lack of knowledge of arterial-specific recruitment patterns. Here we establish the importance of the cathepsin G (CatG) in the context of arterial myeloid cell recruitment.
  
  
  
  Intravital microscopy of the carotid artery, the jugular vein, and cremasteric arterioles and venules in Apoe-/-and CatG-deficient mice (Apoe-/-Ctsg-/-) was used to study site-specific myeloid cell behavior after high-fat diet feeding or tumor necrosis factor stimulation. Atherosclerosis development was assessed in aortic root sections after 4 weeks of high-fat diet, whereas lung inflammation was assessed after inhalation of lipopolysaccharide. Endothelial deposition of CatG and CCL5 was quantified in whole-mount preparations using 2-photon and confocal microscopy.
  
  
  
  Our observations elucidated a crucial role for CatG during arterial leukocyte adhesion, an effect not found during venular adhesion. Consequently, CatG deficiency attenuates atherosclerosis but not acute lung inflammation. Mechanistically, CatG is immobilized on arterial endothelium where it activates leukocytes to firmly adhere engaging integrin clustering, a process of crucial importance to achieve effective adherence under high-shear flow. Therapeutic neutralization of CatG specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of CatG-neutralizing antibodies permitted inhibition of atherogenesis in mice.
  
  
  
  Taken together, these findings present evidence of an arterial-specific recruitment pattern centered on CatG-instructed adhesion strengthening. The inhibition of this process could provide a novel strategy for treatment of arterial inflammation with limited side effects.
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Almudena
authors.initials: A
authors.lastname: Ortega-Gomez
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Melanie
authors.initials: M
authors.lastname: Salvermoser
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Robert
authors.initials: R
authors.lastname: Pick
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Janine
authors.initials: J
authors.lastname: Brauner
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Patricia
authors.initials: P
authors.lastname: Lemnitzer
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Tilgner
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Renske J
authors.initials: RJ
authors.lastname: de Jong
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Remco T A
authors.initials: RT
authors.lastname: Megens
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Janina
authors.initials: J
authors.lastname: Jamasbi
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Döring
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Christine T
authors.initials: CT
authors.lastname: Pham
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheiermann
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Siess
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Maik
authors.initials: M
authors.lastname: Drechsler
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Jochen
authors.initials: J
authors.lastname: Grommes
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.).
authors.forename: Barbara
authors.initials: B
authors.lastname: Walzog
authors.affiliation: From IPEK, LMU Munich, Germany (A.O.-G., J.B., P.L., R.d.J., R.T.A.M., J.J., Y.D., W.S., M.D., C.W., J.G., O.S.); WBex, LMU Munich, Germany (M.S., R.P., C.S., B.W.); Department of Anaesthesiology, University Münster, Germany (J.R., A.Z.); European Vascular Center Aachen-Maastricht, University Hospital RWTH Aachen, Germany (J.T., J.G.); CARIM, Maastricht University, the Netherlands (R.T.A.M., C.W.); DZHK, partner site Munich Heart Alliance, Germany (Y.D., M.D., C.W., O.S.); Department of Medicine, Washington University, St Louis, MO (C.T.P.); and AMC, Department of Pathology, Amsterdam University, the Netherlands (M.D., O.S.). oliver.soehnlein@gmail.com.
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
mesh_terms: D000818:Animals; D001158:Arteries; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers; D056649:Cathepsin G / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D036904:Leukocyte Rolling; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D033081:Shear Strength; D014699:Venules
chemical_list: D015415:Biomarkers; D018946:Chemokine CCL5; D016023:Integrins; D056649:Cathepsin G
keywords: atherosclerosis; cathepsin G; focal adhesions; integrins