Abstract 80: Interleukin 15 Plays an Important Role in the Development of Atherosclerosis in Apolipoprotein E Knockout Mice

IL-15 is an essential cytokine for the development of NK and CD8+T cells and also involved in activation of inflammation in macrophages. Therefore, we hypothesized that IL-15 may affect the development of atherosclerosis via regulating immune/inflammatory cells. To test this we generated apoE KO mice that either overexpressed (il-15TgapoE-/-) or lacked either one (il-15+/-apoE-/-) or both copies (il-15-/-apoE-/-) of the IL-15 gene. Deficiency of IL-15 substantially reduced atherosclerosis in spite of increased plasma lipoprotein cholesterol levels. Interestingly, il-15+/-apoE -/- mice exhibited intermediate levels of atherosclerosis. Conversely, overexpression of IL-15 in il-15tg apoE -/- mice resulted in substantially increased atherosclerosis compared to apoE -/- littermates. Deficiency of IL-15 resulted in a lack of NK cells and reduced populations of monocytes and CD8+ T cells. Correspondingly, reduced levels of CD11b+ and CD8a+ cells were detected in atherosclerotic lesions from il-15-/-apoE -/- mice compared to those from apoE -/- mice. To test the role of NK cells in atherosclerosis, NK1.1+ cells were immune-depleted in apoE -/- mice and lesions size was analyzed. Atherosclerosis was reduced but to a lesser extent than in age matched il-15-/-apoE -/- mice. Plaques from these mice were almost devoid of CD8+T cells. Deletion of a single copy of the il-15 gene (il-15+/-) in NK/NKT cell immunodepleted apoE -/- mice resulted in a further reduction in atherosclerosis, suggesting the involvement NK/NKT and CD8-T cell independent pathways participate in IL-15’s proatherogenic effects. Treatment of macrophages with recombinant IL-15 in vitro induced expression/activity of a variety of pro-inflammatory targets. Furthermore, il-15-/-apoE -/- mice exhibited reduced levels of MCP-1 in plaques and reduced circulating levels of SAA and IL-6, whereas circulating levels of SAA and IL-6 were greatly increased in il-15tg apoE -/- mice compared to apoE -/- littermates. In conclusion IL-15 plays a significant role in promoting atherosclerosis through multiple pathways including promotion of the survival/recruitment of NK/CD8+T cells, as well as the modulation of monocyte levels, and/or direct activation of macrophages.