Depletion of natural killer cell function decreases atherosclerosis in low-density lipoprotein receptor null mice.
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.


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.


CONCLUSIONS
These studies demonstrate that NK cells infiltrate the vessel wall and promote atherosclerotic lesion development.
Departments of Pathology and Laboratory Medicine, University of Ottawa Heart Institute, 40 Ruskin St, Room H259A, Ottawa, Ontario, Canada, K1Y 4W7. swhitman@ottawaheart.ca
Stewart C
SC
Whitman
Debra L
DL
Rateri
Stephen J
SJ
Szilvassy
Wayne
W
Yokoyama
Alan
A
Daugherty
D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D001018:Aortic Diseases / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D001161:Arteriosclerosis / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D004036:Diet, Atherogenic; D005260:Female; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics; D007249:Inflammation; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011828:Radiation Chimera; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D055630:Receptors, NK Cell Lectin-Like
D000950:Antigens, Ly; C527088:Klra1 protein, mouse; D037181:Lectins, C-Type; D008055:Lipids; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011973:Receptors, LDL; D055630:Receptors, NK Cell Lectin-Like