CELLULAR AND MOLECULAR MECHANISMS BY WHICH INTERLEUKIN-15 CONTRIBUTES TO ATHEROSCLEROSIS

Abstract

Interleukin-15 is a well known pro-inflammatory cytokine which regulates many activities of immune cells including macrophages, CD8 T, natural killer, and natural killer T cells. All these cell types have been shown to contribute to atherogenesis. Here we report that Interleukin-15 plays a key role in the progression of atherosclerosis in both aortic sinus and coronary arteries. Mice lacking Interleukine-15 had lower levels of atherosclerosis while mice overexpressing Interleukin-15 had increased plaque size. We also showed that this effect on atherosclerosis is partially independent of natural killer, natural killer T, and CD8 T cells. Immunodepletion of NK1.1+ cells led to less atherosclerosis in IL-15+/- ApoE-/- compared with IL-15+/+ ApoE-/- mice. Furthermore the absence of IL-15 in IL15-/- ApoE-/- mice resulted in lower expression of MCP-1 and less presence of CD11b+ cells in plaques compared with ApoE-/- control mice. In addition, in vitro treatment of macrophages with Interleukin-15 increased the expression of inflammatory cytokines, while a soluble Interleukin-15 receptor α suppressed the pro-inflammatory effects of Interleukin-15. These findings are consistent with others’ findings that Interleukine-15 affects macrophages through Interleukin-15 receptor α. To further examine this in vivo, we transplanted bone marrow from wild-type or Interleukin-15 receptor α knockout mice into LDLR-/- recipients. Mice lacking Interleukin-15 receptor α in their bone marrow derived cells developed smaller plaques. Also, we confirmed that Interleukin-15’s pro-inflammatory effect in macrophages isolated from Interleukin-15 receptor α knockout mice was partially suppressed, in comparison with macrophages isolated from wild-type mice. It has been shown that the absence of HDL receptor (SR-BI) and ApoE in SR-BI/ApoE dKO mice leads to severe coronary artery atherosclerosis and consequently heart attack. We demonstrated that a lack of Interleukin-15 in IL-15/SR-BI/ApoE tKO mice, improved the survival of these mice compared with SR-BI/ApoE dKO control animals and also reduced the levels of atherosclerosis both in aortic sinus and coronary arteries. In conclusion, these findings indicate that Interleukin-15 promotes atherosclerosis through multiple cellular and molecular mechanisms including monocyte/macrophage activation and survival/maturation of natural killer and CD8 T cells.