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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 35; no. 11; pp. 2316 - 2325
• Main Authors: Chaudhari, Sweena M, Sluimer, Judith C, Koch, Miriam, Theelen, Thomas L, Manthey, Helga D, Busch, Martin, Caballero-Franco, Celia, Vogel, Frederick, Cochain, Clément, Pelisek, Jaroslav, Daemen, Mat J, Lutz, Manfred B, Görlach, Agnes, Kissler, Stephan, Hermanns, Heike M, Zernecke, Alma
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.11.2015
• Subjects: 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; Carotid Artery Diseases - metabolism; CD11c Antigen - genetics; CD11c Antigen - 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; Signal Transduction; STAT3 Transcription Factor - metabolism; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; atherosclerosis; leukocytes; antigen-presenting cells; diet; high-fat; inflammation
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.115.306171

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.