Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease.
To clarify the link between autoimmune disease and hypercholesterolemia, we created the gld.apoE(-/-) mouse as a model of accelerated atherosclerosis. Atherosclerotic lesion area was significantly increased in gld.apoE(-/-) mice compared with apoE(-/-) mice. gld.apoE(-/-) mice also displayed increases in lymphadenopathy, splenomegaly, and autoantibodies compared with gld mice, and these effects were exacerbated by high cholesterol diet. gld.apoE(-/-) mice exhibited higher levels of apoptotic cells, yet a reduced frequency of engulfed apoptotic nuclei within macrophages. Infusion of lysophosphatidylcholine, a component of oxidized low density lipoprotein, markedly decreased apoptotic cell clearance in gld mice, indicating that hypercholesterolemia promotes autoimmune disease in this background. These data suggest that defects in apoptotic cell clearance promote synergy between atherosclerotic and autoimmune diseases.
Aprahamian
Tamar
T
Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany St., W611, Boston, MA 02118, USA.
Rifkin
Ian
I
Bonegio
Ramon
R
Hugel
Bénédicte
B
Freyssinet
Jean-Marie
JM
Sato
Kaori
K
Castellot
John J
JJ
Walsh
Kenneth
K
D000818:Animals; D001011:Aorta / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000276:immunology*; D001161:Arteriosclerosis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D001483:Base Sequence; D002784:Cholesterol / Q000097:blood; D017931:DNA Primers / Q000235:genetics; D053222:Fas Ligand Protein; D006937:Hypercholesterolemia / Q000209:etiology / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010641:Phenotype
D001057:Apolipoproteins E; D017931:DNA Primers; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D002784:Cholesterol