IL-27 Receptor Limits Atherosclerosis in Ldlr-/- Mice
Rationale: Atherosclerosis is a chronic inflammatory disease of the arterial wall. Several pro-inflammatory cytokines are known to promote atherosclerosis, but less is known about the physiological role of anti-inflammatory cytokines. IL-27 is a recently discovered member of the IL-6/IL-12 family. The IL-27 receptor (IL-27R) is composed of IL-27RA (WSX-1) and gp130 and 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: To test the role of IL-27R 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 TNF. Several chemokines, including CCL2 were up regulated 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 Th17 resulting in increased production of IL-17A and TNF, which in turn enhances chemokine expression and drives the accumulation of pro-atherogenic myeloid cells in atherosclerotic aortas. These findings establish a novel anti-atherogenic role of IL-27R signaling, which acts to suppress the production of pro-inflammatory cytokines and chemokines and to curb the recruitment of inflammatory myeloid cells into atherosclerotic aortas.
- Received July 13, 2012.
- Accepted August 27, 2012.
- Copyright © 2012, American Heart Association