Subject codes: [130] Animal models of human disease [134] Pathophysiology [135] Risk Factors [137] Cell biology/structural biology [142] Cell biology/structural biology [90] Lipid and lipoprotein metabolism ABSTRACT Rationale: Apoptosis and fatty acid-binding protein-4 (FABP4) induced-endoplasmic reticulum (ER) stress in macrophage is an important pathological process in several vascular occlusive diseases, including atherosclerosis, both of which are accelerated by lipids or inflammatory

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... nes. Objective: To determine whether interleukin 17A (IL-17A) accelerates atherosclerosis through activating FABP4-mediated ER stress in macrophage. Methods and Results: We show here that IL-17A induced ER stress in both murine and human-derived macrophages in vitro, and in the atherosclerotic lesions of ApoE-/-mice. Treating ApoE-/-mice with a chemical chaperone alleviated IL-17A-mediated ER stress and macrophage apoptosis, which was accompanied by recovered atherogenesis. Mechanistically, IL-17A up-regulated the expression of FABP4 (aP2), a cytosolic lipid chaperone that is able to promote lipid-induced macrophage ER stress, through NF-B and ERK/p38 mitogen-activated protein kinase (MAPK) pathways in macrophages. The inhibition of aP2 expression with a specific chemical inhibitor significantly blocked IL-17A-accelerated ER stress and apoptosis in plaque, and partially rescued IL17A-induced atherogenesis. Conclusions: The data collectively establish a previously unrecognized link between IL-17A and ER stress through cytosolic lipid chaperone aP2 in macrophages and provide a new insight for understanding the role of IL-17A in atherosclerosis.