Abstract
Interleukin- (IL-) 35, a novel functional cytokine of regulatory T cells (Treg) comprised of the IL-12p35 subunit and the other subunit Epstein-Barr virus-induced gene 3 (EBI3), regulates the activity of CD4+ T cells and macrophages, thereby playing a critical role in inflammatory and autoimmune diseases. Previous studies demonstrated that both recombinant mice and human IL-35 attenuated atherosclerosis in ApoE-/- mice. Additionally, EBI3 deficiency enhanced the activation of macrophages and increased atherosclerotic lesions in LDLR-/- mice. This study generated double-deficient mice for ApoE and IL-12p35 (ApoE-/- IL-12p35-/- mice) and investigated the effect of IL-12p35 deficiency on atherosclerosis. IL-12p35 deficiency alleviated Th1/Th2 imbalance, aggravated Th17/Treg imbalance, and attenuated atherosclerotic plaque formation in ApoE-/- mice. Additionally, exogenous rIL-35 treatment reversed the imbalance of Th17/Treg and attenuated atherosclerosis in ApoE-/- mice. These findings suggest that IL-12p35 deficiency ameliorates atherosclerosis in ApoE-/- mice, partially, via attenuating the Th1/Th2 imbalance, although IL-12p35 deficiency aggravates the Th17/Treg imbalance.
Highlights
Atherosclerosis is a common clinical disease which is caused by multifactorial factors and leads to different degrees of vascular stenosis and blockage and clinical manifestations
The atherosclerotic plaque of each mouse by oil red O straining and the results showed that in HDF-fed ApoE-/mice, IL-12p35 deficiency significantly reduced the atherosclerotic plaque approximately 35% in the aortic trees (ApoE-/- group: 41 ± 12% vs. ApoE-/- IL-12p35-/- group: 27 ± 9%, Figure 1(a)), while exhibiting a reduction of approximately 26% atherosclerotic plaque in the aortic root (ApoE-/mouse group: 0 61 ± 0 14 mm2 vs. ApoE-/- IL-12p35-/mouse group: 0 44 ± 0 13 mm2, Figure 1(b))
The serum lipid levels and body weight in different time points after the mice were fed a HDF were measured; the results showed that no difference of total cholesterol (TC), TG, HDL-C, and low-density lipoprotein cholesterol (LDL-C) levels and body weight were observed in weeks 8, 18, and 24
Summary
Atherosclerosis is a common clinical disease which is caused by multifactorial factors and leads to different degrees of vascular stenosis and blockage and clinical manifestations. Accumulating evidence demonstrated that both Th1 and Th17 responses played a pathogenic role in atherosclerosis, while IFN-γ or IL-17 deficiency alone ameliorated atherosclerosis in ApoE-/- mice [4,5,6,7]. Other Th2-type cytokines such as IL-5, IL-13, and IL-33 were found to protect mice from atherosclerosis [10,11,12,13,14] Taken together, these reports indicated a complex role of Th2 immune response in atherosclerosis. We found that circulating IL-35 concentrations significantly decreased in patients with coronary artery disease [24] This evidence indicated that IL-35 is involved in the regulation of human atherosclerosis. This study generated double-deficient mice for ApoE and IL-12p35 (ApoE-/- IL-12p35-/- mice) and investigated the role of IL-12p35 deficiency in atherosclerosis
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