Depletion of Natural Killer Cell Function Decreases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice

Abstract

Objective— Natural killer (NK) cells are a key component of innate immunity. Despite being identified in human and mouse atherosclerotic lesions, the role of NK cells in the disease process in unknown. To determine this role, we created chimeric atherosclerosis-susceptible low-density lipoprotein (LDL) receptor null (ldl-r^−/−) mice that were deficient in functional NK cells through expression of a transgene encoding for Ly49A. Methods and Results— Bone marrow cells from Ly49A transgenic and nontransgenic littermates were used to repopulate the hematopoietic system of lethally-irradiated female ldl-r^−/− mice. After a recovery period to permit sufficient engraftment, mice were placed on a diet enriched in saturated fat and cholesterol. After 8 weeks, there was no difference in either serum total cholesterol concentrations or lipoprotein cholesterol distribution in mice repopulated with nontransgenic versus Ly49A transgenic marrow cells. Using immunohistochemistry, we detected NK cells in atherosclerotic lesions of both groups of mice. However, deficiency of functional NK cells significantly reduced the size of atherosclerosis by 70% (P=0.0002) in cross-sectional analysis of the aortic root and by 38% (P=0.004) in en face analysis of the intimal surface of the aortic arch. Conclusion— These studies demonstrate that NK cells infiltrate the vessel wall and promote atherosclerotic lesion development. Natural killer (NK) cells are found in atherosclerotic lesions, yet their role in the disease process is unknown. Using bone marrow transplantation, we created atherosclerosis-susceptible mice that were deficient in functional NK cells. NK cell deficiency did not affect serum cholesterol values but did significantly reduce (70%) atherosclerotic lesion formation.