Deficiency of HIF1α in Antigen-Presenting Cells Aggravates Atherosclerosis and Type 1 T-Helper Cell Responses in Mice
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 T-helper cells. Overexpression of STAT3 in Hif1a-deficient APCs in bone marrow reversed enhanced atherosclerotic lesion formation and reduced T-helper 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 T-helper 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.
- Received July 6, 2015.
- Accepted September 14, 2015.
- © 2015 American Heart Association, Inc.