Distinct roles for complement in glomerulonephritis and atherosclerosis revealed in mice with a combination of lupus and hyperlipidemia

Objective Although the accelerating effect of systemic lupus erythematosus (SLE) on atherosclerosis is well established, the underlying mechanisms are unknown. The aim of this study was to explore the hypothesis that lupus autoimmunity modulates the effect of hypercholesterolemia in driving arterial pathologic development. >Methods Low-density lipoprotein receptor–deficient (Ldlr(−/−)) mice were crossed with B6.129-Sle16 (Sle16)–congenic autoimmune mice to obtain Sle16. Ldlr(−/−) mice, which were compared with Ldlr(−/−) and Sle16 control mice. All mice were fed either a low-fat or high-fat diet. Groups of mice were compared, by strain and by diet group, for features of accelerated atherosclerosis and autoimmunity. Results Presence of the Sle16 locus significantly increased the extent of atherosclerosis in Ldlr(−/−) mice. Circulating C3 levels were significantly reduced in Sle16.Ldlr(−/−) mice compared to Ldlr(−/−) control mice and this was paralleled by a marked reduction in arterial lesion C3 deposition despite similar levels of IgG deposition between the groups. Increased numbers of apoptotic cells in plaques were observed in the high-fat–fed Sle16.Ldlr(−/−) mice, consistent with the observed defective clearance of cellular debris. After receiving the high-fat diet, Sle16.Ldlr(−/−) mice developed glomerulonephritis and displayed enhanced glomerular C3 deposition. Conclusion These results indicate that accelerated atherosclerosis and renal inflammation in SLE are closely linked via immune complex formation and systemic complement depletion. However, whereas hyperlipidemia will enhance renal immune complex–mediated complement activation and the development of nephritis, accelerated atherosclerosis is, instead, related to complement depletion and a reduction in the uptake of apoptotic/necrotic debris. These results suggest that aggressive treatment of hyperlipidemia in patients with SLE may reduce the occurrence of lupus nephritis, as well as diminish the risk of accelerated atherosclerosis.