Deficiency of HIF1 alpha in Antigen-Presenting Cells Aggravates Atherosclerosis and Type 1 T-Helper Cell Responses in Mice

Sweena M. Chaudhari, Judith C. Sluimer, Miriam Koch, Thomas L. Theelen, Helga D. Manthey, Martin Busch, Celia Caballero-Franco, Frederick Vogel, Clement Cochain, Jaroslav Pelisek, Mat J. Daemen, Manfred B. Lutz, Agnes Goerlach, Stephan Kissler, Heike M. Hermanns, Alma Zernecke*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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)-1 in APCs in atherosclerosis. Approach and Results We found upregulated HIF1 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. HIF1 directly controls Signal Transducers and Activators of Transcription 3 (Stat3), and a reduced STAT3 expression was found in HIF1-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, HIF1, STAT3, and interleukin-12 protein were found to colocalize with APCs. Conclusions Our findings identify HIF1 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.
Original languageEnglish
Pages (from-to)2316-2325
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume35
Issue number11
DOIs
Publication statusPublished - Nov 2015

Keywords

  • antigen-presenting cells
  • atherosclerosis
  • diet
  • high-fat
  • inflammation
  • leukocytes

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