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 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 infstantiate the critical role of APCs in controlling immune mechanisms that drive atherosclerotic lesion development.