复旦研究生《细胞免疫》atherosclerosis macrophage.pdfVIP

The Journal of Immunology IL-17A In?uences Essential Functions of the Monocyte/Macrophage Lineage and Is Involved in Advanced Murine and Human Atherosclerosis Christian Erbel,* Mohammadreza Akhavanpoor,* Deniz Okuyucu,* Susanne Wangler,* Alex Dietz,* Li Zhao,* Konstantinos Stellos,? Kristina M. Little,? Felix Lasitschka,x Andreas Doesch,* Maani Hakimi,{,‖ Thomas J. Dengler,# Thomas Giese,** Erwin Blessing,* Hugo A. Katus,*,?? and Christian A. Gleissner* Atherosclerosis is a chronic in?ammatory disease. Lesion progression is primarily mediated by cells of the monocyte/macrophage lineage. IL-17A is a proin?ammatory cytokine, which modulates immune cell traf?cking and is involved in?ammation in (auto)immune and infectious diseases. But the role of IL-17A still remains controversial. In the current study, we investigated effects of IL-17A on advanced murine and human atherosclerosis, the common disease phenotype in clinical care. The 26-wk-old apolipoprotein E–de?cient mice were fed a standard chow diet and treated either with IL-17A mAb (n = 15) or irrelevant Ig (n = 10) for 16 wk. Furthermore, essential mechanisms of IL-17A in atherogenesis were studied in vitro. Inhibition of IL-17A markedly prevented atherosclerotic lesion progres- sion (p = 0.001) by reducing in?ammatory burden and cellular in?ltration (p = 0.01) and improved lesion stability (p = 0.01). In vitro experiments showed that IL-17A plays a role in chemoattractance, monocyte adhesion, and sensitization of APCs toward pathogen- derived TLR4 ligands. Also, IL-17A induced a unique transcriptome pattern in monocyte-derived macrophages distinct from known macrophage types. Stimulation of human carotid plaque tissue ex vivo with IL-17A induced a proin?ammatory milieu and upregulation of molecules expressed by the IL-17A–induced macrophage subtype. In this study, we show that functional blockade of IL-17A prevents atherosclerotic lesion progression and induces pl