title: Deficiency of HIF1α in Antigen-Presenting Cells Aggravates Atherosclerosis and Type 1 T-Helper Cell Responses in Mice.
abstract: OBJECTIVE
  Although immune responses drive the pathogenesis of atherosclerosis, mechanisms that control antigen-presenting cell (APC)-mediated immune activation in atherosclerosis remain elusive. We here investigated the function of hypoxia-inducible factor (HIF)-1α in APCs in atherosclerosis.
  
  
  RESULTS
  We found upregulated HIF1α expression in CD11c(+) APCs within atherosclerotic plaques of low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. Conditional deletion of Hif1a in CD11c(+) APCs in high-fat diet-fed Ldlr(-/-) mice accelerated atherosclerotic plaque formation and increased lesional T-cell infiltrates, revealing a protective role of this transcription factor. HIF1α directly controls Signal Transducers and Activators of Transcription 3 (Stat3), and a reduced STAT3 expression was found in HIF1α-deficient APCs and aortic tissue, together with an upregulated interleukin-12 expression and expansion of type 1 T-helper (Th1) cells. Overexpression of STAT3 in Hif1a-deficient APCs in bone marrow reversed enhanced atherosclerotic lesion formation and reduced Th1 cell expansion in chimeric Ldlr(-/-) mice. Notably, deletion of Hif1a in LysM(+) bone marrow cells in Ldlr(-/-) mice did not affect lesion formation or T-cell activation. In human atherosclerotic lesions, HIF1α, STAT3, and interleukin-12 protein were found to colocalize with APCs.
  
  
  CONCLUSIONS
  Our findings identify HIF1α to antagonize APC activation and Th1 T cell polarization during atherogenesis in Ldlr(-/-) mice and to attenuate the progression of atherosclerosis. These data substantiate the critical role of APCs in controlling immune mechanisms that drive atherosclerotic lesion development.
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Sweena M
authors.initials: SM
authors.lastname: Chaudhari
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Judith C
authors.initials: JC
authors.lastname: Sluimer
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Miriam
authors.initials: M
authors.lastname: Koch
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Theelen
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Helga D
authors.initials: HD
authors.lastname: Manthey
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Martin
authors.initials: M
authors.lastname: Busch
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Celia
authors.initials: C
authors.lastname: Caballero-Franco
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Frederick
authors.initials: F
authors.lastname: Vogel
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Clément
authors.initials: C
authors.lastname: Cochain
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Pelisek
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Mat J
authors.initials: MJ
authors.lastname: Daemen
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Manfred B
authors.initials: MB
authors.lastname: Lutz
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Agnes
authors.initials: A
authors.lastname: Görlach
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Stephan
authors.initials: S
authors.lastname: Kissler
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.).
authors.forename: Heike M
authors.initials: HM
authors.lastname: Hermanns
authors.affiliation: From the Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg (S.M.C., M.K., C.C., A.Z.), Rudolf Virchow Center (H.D.M., M.B., H.M.H.), Institute of Virology and Immunobiology (M.B.L.), and Division of Hepatology, Medical Clinic II, University Hospital Würzburg (H.M.H.), University of Würzburg, Würzburg, Germany; Department of Pathology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands (J.C.S., T.L.T.); Joslin Diabetes Center, Harvard Medical School, Boston, MA (C.C.-F., S.K.); Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, TU Munich, Munich, Germany (F.V., A.G.); Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany (J.P.); and Department of Pathology, Amsterdam Medical Centre, Amsterdam, The Netherlands (M.J.D.). alma.zernecke@uni-wuerzburg.de.
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism*; D001011:Aorta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*
chemical_list: D039521:CD11c Antigen; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011973:Receptors, LDL; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D018664:Interleukin-12
keywords: antigen-presenting cells; atherosclerosis; diet; high-fat; inflammation; leukocytes