on May 30, 2002
Published online before print May 30, 2002, doi: 10.1161/01.ATV.0000024082.46387.38
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Submitted on April 10, 2002
Accepted on May 16, 2002
Inflammation in Atherosclerosis. Lesion Formation in LDL Receptor--Deficient Mice With Perforin and Lystbeige Mutations
Natalie K. Schiller ;
From The Scripps Research Institute, Department of Immunology, La Jolla, Calif.
* To whom correspondence should be addressed. E-mail: lcurtiss{at}scripps.edu.
Objective—Natural killer (NK) cells have been identified in human vascular pathologies. In this study, we identified NK cells in aortic root atherosclerotic lesions of low density lipoprotein (LDL) receptor--deficient (LDLr-/-) mice. To characterize the role of NK cell--mediated cytolysis in atherosclerosis, we generated C57Bl/6 double-mutant mice by crossing LDLr-/- mice with NK cell--defective Lystbeige mice (creating beige,LDLr-/- mice) and with perforin-deficient mice (creating Pfp-/-,LDLr-/- mice).
Methods and Results—Male mice (8 to 10 weeks old) were fed a high-fat diet to induce atherosclerosis. Compared with LDLr-/- mice, beige,LDLr-/- mice had impaired NK cell cytolytic activity and significantly increased atherosclerosis (P<0.05). Pfp-/-,LDLr-/- mice had impaired NK cell cytolytic activity, yet they had lesions that were similar to those of control mice. This suggested that NK cell cytolysis did not play a significant role in atherosclerosis and that the exacerbated atherosclerosis of the beige,LDLr-/- mouse was independent of impaired NK cell cytolytic activity. Therefore, we investigated the role of T and B lymphocytes in atherosclerosis of beige mice by crossing them with recombinase activator gene 1--deficient LDLr-/- mice (Rag1-/-,LDLr-/- mice), thus creating beige,Rag1-/-,LDLr-/- mice. As in the double-mutant study, beige,Rag1-/-,LDLr-/- mice had significantly increased lesions compared with Rag1-/-,LDLr-/- control mice.
Conclusions—Therefore, the Lystbeige mutation in LDLr-/- mice has proatherogenic properties that are independent of NK cell--mediated cytolysis and lymphocyte-mediated acquired immunity.
Key words: atherosclerosis • perforin • Chédiak-Higashi syndrome • lysosome • natural immunity
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