4.7 Article

Interleukin-27 Receptor Limits Atherosclerosis in Ldlr-/- Mice

Journal

CIRCULATION RESEARCH
Volume 111, Issue 10, Pages 1274-U118

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.112.277525

Keywords

atherosclerosis; chemokines; cytokines; inflammation; leukocyte recruitment; vascular inflammation

Funding

  1. National Institutes of Health [HL 115232, HL 55798, AI 89624]
  2. American Heart Association [10POST4160142-01]
  3. Deutsche Forschungsgemeinschaft

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Rationale: 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. Objective: The aim of this study was to test the role of IL-27 receptor signaling in immune cells in atherosclerosis development. Methods and Results: 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. Conclusions: 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. (Circ Res. 2012;111:1274-1285.)

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