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 cytokines.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-κB 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.

中文翻译：

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白细胞介素17A通过促进脂肪酸结合蛋白4介导的巨噬细胞内质网应激而加剧动脉粥样硬化。

理由： 巨噬细胞中的凋亡和脂肪酸结合蛋白4（FABP4）诱导的内质网（ER）应激是几种血管闭塞性疾病（包括动脉粥样硬化）的重要病理过程，两者均由脂质或炎性细胞因子加速。客观的： 确定白细胞介素17A（IL-17A）是否通过激活巨噬细胞中FABP4介导的内质网应激来加速动脉粥样硬化。方法和结果：我们在这里显示IL-17A诱导小鼠和人类衍生的巨噬细胞在体外，以及在ApoE-/-小鼠的动脉粥样硬化病变中的内质网应激。用化学伴侣治疗ApoE-/-小鼠可减轻IL-17A介导的内质网应激和巨噬细胞凋亡，并伴有动脉粥样硬化的恢复。机械上，IL-17A通过NF-κB和ERK / p38丝裂原活化蛋白激酶（MAPK）途径上调FABP4（aP2）的表达，FABP4（aP2）能够促进脂质诱导的巨噬细胞ER应激。巨噬细胞。用特定的化学抑制剂抑制aP2表达可显着阻断斑块中IL-17A加速的ER应激和细胞凋亡，并部分挽救了IL17A诱导的动脉粥样硬化。结论： 该数据通过巨噬细胞中的胞质脂质伴侣aP2共同建立了IL-17A和ER应激之间以前无法识别的联系，并为了解IL-17A在动脉粥样硬化中的作用提供了新的见解。