Abstract
Myeloid cells, key players in atherosclerosis, take up and present antigens, leading to systemic and local T cell activation. The recruitment and activation of immune cells to the aorta in atherosclerosis is regulated by adhesion molecules, chemokines and cytokines. IL-27R is an immunoregulatory signaling nod in autoimmune and infectious pathologies. IL-27R was shown to suppress T cells activation in atherosclerosis, however it’s possible role in myeloid cell accumulation and activation is not understood. Here we demonstrate that Apoe−/−Il27ra−/− mice fed with “Western Diet” for 7 or 18 weeks developed significantly more atherosclerosis compared to Apoe−/−Il27ra+/− controls. Accelerated disease was driven by enhanced expression of adhesion molecules and chemokines causing the accumulation of immune cells. Myeloid cells produced more inflammatory cytokines and upregulated MHCII. Multiphoton microscopy revealed more efficient interactions between aortic myeloid cells and CD4+ T cells. Overall, we show that IL-27R signaling controls endothelial cells activation and myeloid cell recruitment at early and advanced stages of atherosclerosis. In the absence of IL-27R myeloid cells become hyperactivated, produce pro-inflammatory cytokines and act as more potent antigen presenting cells. Enhanced interactions between Il27ra−/− APC and CD4+ T cells in the aortic wall contribute to T cells re-activation and pro-atherogenic cytokine production.
Highlights
Atherosclerosis is a lipid-driven chronic inflammatory disease characterized by progressive atherosclerotic plaque growth accompanied by the accumulation, local proliferation and activation of various immune cells in the vessel wall[1, 2]
T regulatory (Treg) cells survival and functions are dependent on IL-27 receptor (IL-27R) signaling, both suppressive and activating role of IL-27R signaling on Tregs were reported by different groups[27, 28], perhaps reflecting differences in mouse models used in the studies
In vitro studies demonstrated that IL-27 promotes inflammatory gene expression in myeloid cells, in vivo data suggest suppressive role of IL-27R signaling as determined by the enhanced MHCII expression on dendritic cells (DC) isolated from Il27ra−/− mice[30]
Summary
Atherosclerosis is a lipid-driven chronic inflammatory disease characterized by progressive atherosclerotic plaque growth accompanied by the accumulation, local proliferation and activation of various immune cells in the vessel wall[1, 2]. Cells accumulated in atherosclerotic plaques and surrounding tissues produce various “mediators of inflammation” such as cytokines and chemokines, fueling local inflammation and promoting atherosclerosis[3,4,5,6]. Ebi[3] heterodimerizes with IL-12p35 to form IL-35, another anti-inflammatory cytokine[21], while the p28 subunit potentially forms a homodimer[22] or binds with cytokine-like factor 1(CLF) to produce p28/CLF, a complex that engages IL-6R23. Because of such complexity, IL-27R deficient mice (lacking Il27ra gene) represent the best tool to address the role of IL-27R signaling in various physiological settings. In vitro studies demonstrated that IL-27 promotes inflammatory gene expression in myeloid cells, in vivo data suggest suppressive role of IL-27R signaling as determined by the enhanced MHCII expression on dendritic cells (DC) isolated from Il27ra−/− mice[30]
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