Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Circ Res. 2012 Oct 26;111(10):1274-85. doi: 10.1161/CIRCRESAHA.112.277525. Epub 2012 Aug 27.
Atherosclerosis is a chronic inflammatory disease of the arterial wall. Several proinflammatory cytokines are known to promote atherosclerosis, but less is known about the physiological role of anti-inflammatory cytokines. Interleukin (IL)-27 is a recently discovered member of the IL-6/IL-12 family. The IL-27 receptor is composed of IL-27 receptor A (WSX-1) and gp130 and is required for all established IL-27 signaling pathways. The expression of the IL-27 subunit Ebi3 is elevated in human atheromas, yet its function in atherosclerosis remains unknown.
The aim of this study was to test the role of IL-27 receptor signaling in immune cells in atherosclerosis development.
Atherosclerosis-prone Ldlr(-/-) mice transplanted with Il27ra(-/-) bone marrow and fed Western diet for 16 weeks developed significantly larger atherosclerotic lesions in aortic roots, aortic arches, and abdominal aortas. Augmented disease correlated with increased accumulation of CD45(+) leukocytes and CD4(+) T cells in the aorta, which produced increased amounts of IL-17A and tumor necrosis factor. Several chemokines, including CCL2, were upregulated in the aortas of Ldlr(-/-) mice receiving Il27ra(-/-) bone marrow, resulting in accumulation of CD11b(+) and CD11c(+) macrophages and dendritic cells in atherosclerotic aortas.
The absence of anti-inflammatory IL-27 signaling skews immune responses toward T-helper 17, resulting in increased production of IL-17A and tumor necrosis factor, which in turn enhances chemokine expression and drives the accumulation of proatherogenic myeloid cells in atherosclerotic aortas. These findings establish a novel antiatherogenic role for IL-27 receptor signaling, which acts to suppress the production of proinflammatory cytokines and chemokines and to curb the recruitment of inflammatory myeloid cells into atherosclerotic aortas.
动脉粥样硬化是动脉壁的一种慢性炎症性疾病。已知几种促炎细胞因子可促进动脉粥样硬化，但关于抗炎细胞因子的生理作用知之甚少。白细胞介素（IL）-27 是最近发现的 IL-6/IL-12 家族成员。IL-27 受体由 IL-27 受体 A（WSX-1）和 gp130 组成，是所有已建立的 IL-27 信号通路所必需的。Ebi3 亚基的 IL-27 在人类动脉粥样硬化斑块中表达升高，但在动脉粥样硬化中的作用尚不清楚。
本研究旨在检测 IL-27 受体信号在动脉粥样硬化发展过程中免疫细胞中的作用。
易患动脉粥样硬化的 LDLR(-/-) 小鼠接受 IL-27ra(-/-) 骨髓移植并接受西方饮食 16 周后，主动脉根部、主动脉弓和腹主动脉的动脉粥样硬化病变明显增大。疾病的加重与主动脉中 CD45(+)白细胞和 CD4(+)T 细胞的积累增加相关，这些细胞产生了更多的 IL-17A 和肿瘤坏死因子。在接受 IL-27ra(-/-)骨髓移植的 LDLR(-/-)小鼠的主动脉中，几种趋化因子（包括 CCL2）上调，导致 CD11b(+)和 CD11c(+)巨噬细胞和树突状细胞在动脉粥样硬化主动脉中的积累。
缺乏抗炎性的 IL-27 信号会使免疫反应偏向辅助性 T 细胞 17，导致 IL-17A 和肿瘤坏死因子的产生增加，进而增强趋化因子的表达，并驱动促动脉粥样硬化的髓样细胞在动脉粥样硬化主动脉中的积累。这些发现确立了 IL-27 受体信号的一种新的抗动脉粥样硬化作用，其作用是抑制促炎细胞因子和趋化因子的产生，并抑制炎症性髓样细胞进入动脉粥样硬化主动脉。
