Inactivation of interleukin-15 reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice

Interleukin (IL)-15 is essential for the survival and maturation of natural killer (NK) and CD8⁺ T cells, and it directly activates macrophages.

In the present study, we examined the effects of inactivating Il-15 on atherosclerosis in apolipoprotein (apo) E-deficient mice.

As expected, Il-15 deficiency reduced circulating NK and CD8⁺ T cells in ApoE^-/- mice. It also increased body weights in female but not male ApoE^-/- mice and increased plasma total cholesterol levels in both. Despite this, the Il-15 knockout reduced spontaneous atherosclerotic plaque development in both male and female ApoE^-/- mice (fed a normal diet) at 25 weeks of age, and in female normal diet-fed ApoE^-/- mice at 15 weeks but not at 38 weeks of age. Furthermore, Il-15 knockout did not impact the levels of atherosclerosis in 25-week-old female ApoE^-/- mice fed a high-fat, high-cholesterol diet for 15 weeks. However, the 6-week treatment with an antibody (M96) that blocks IL-15's interaction with the IL-2Rβγ_c complex but does not interfere with its interaction with IL-15Rα reduced spontaneous atherosclerosis in female ApoE^-/- mice. ApoE knockout mice in which IL-15 was inactivated or neutralized with an antibody exhibited reduced accumulation of CD11b⁺ and CD8⁺ cells within atherosclerotic plaques. These findings demonstrate that interfering with IL-15 signaling through the IL-2Rβγ_c complex delays spontaneous atherosclerosis development in ApoE-deficient mice.