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

Arterioscler Thromb Vasc Biol. 2015 Nov;35(11):2316-25. doi: 10.1161/ATVBAHA.115.306171. Epub 2015 Sep 24.

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.

Approach and 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.

Keywords: antigen-presenting cells; atherosclerosis; diet; high-fat; inflammation; leukocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism*
  • Aorta / immunology
  • Aorta / metabolism*
  • Aorta / pathology
  • Aortic Diseases / genetics
  • Aortic Diseases / immunology
  • Aortic Diseases / metabolism*
  • Aortic Diseases / pathology
  • Atherosclerosis / genetics
  • Atherosclerosis / immunology
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • CD11c Antigen / genetics
  • CD11c Antigen / metabolism
  • Carotid Artery Diseases / metabolism
  • Cells, Cultured
  • Coculture Techniques
  • Diet, High-Fat
  • Disease Models, Animal
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / deficiency*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Interleukin-12 / metabolism
  • Lymphocyte Activation
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Plaque, Atherosclerotic
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism*

Substances

  • CD11c Antigen
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, LDL
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Interleukin-12