Deficiency of HIF1α in Antigen-Presenting Cells Aggravates Atherosclerosis and Type 1 T-Helper Cell Responses in Mice

DOI Web Site 被引用文献3件
  • Sweena M. Chaudhari
    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.);...
  • Judith C. Sluimer
    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.);...
  • Miriam Koch
    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.);...
  • Thomas L. Theelen
    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.);...
  • Helga D. Manthey
    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.);...
  • Martin Busch
    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.);...
  • Celia Caballero-Franco
    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.);...
  • Frederick Vogel
    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.);...
  • Clément Cochain
    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.);...
  • Jaroslav Pelisek
    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.);...
  • Mat J. Daemen
    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.);...
  • Manfred B. Lutz
    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.);...
  • Agnes Görlach
    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.);...
  • Stephan Kissler
    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.);...
  • Heike M. Hermanns
    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.);...
  • Alma Zernecke
    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.);...

抄録

<jats:sec><jats:title>Objective—</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Approach and Results—</jats:title><jats:p>We found upregulated HIF1α expression in CD11c<jats:sup>+</jats:sup>APCs within atherosclerotic plaques of low-density lipoprotein receptor–deficient (<jats:italic>Ldlr</jats:italic><jats:sup>−/−</jats:sup>) mice. Conditional deletion of<jats:italic>Hif1a</jats:italic>in CD11c<jats:sup>+</jats:sup>APCs in high-fat diet–fed<jats:italic>Ldlr</jats:italic><jats:sup>−/−</jats:sup>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 (<jats:italic>Stat3</jats:italic>), 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<jats:italic>Hif1a</jats:italic>-deficient APCs in bone marrow reversed enhanced atherosclerotic lesion formation and reduced Th1 cell expansion in chimeric<jats:italic>Ldlr</jats:italic><jats:sup>−/−</jats:sup>mice. Notably, deletion of<jats:italic>Hif1a</jats:italic>in LysM<jats:sup>+</jats:sup>bone marrow cells in<jats:italic>Ldlr</jats:italic><jats:sup>−/−</jats:sup>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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions—</jats:title><jats:p>Our findings identify HIF1α to antagonize APC activation and Th1 T cell polarization during atherogenesis in<jats:italic>Ldlr</jats:italic><jats:sup>−/−</jats:sup>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.</jats:p></jats:sec>

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