Statin Inhibition of Fc Receptor–Mediated Phagocytosis by Macrophages Is Modulated by Cell Activation and Cholesterol

Abstract

Objectives-An inflammatory response to altered lipoproteins that accumulate in the arterial wall is a major component of the pathogenesis of atherosclerosis. Statins reduce plasma levels of low-density lipoprotein (LDL) and are effective treatments for atherosclerosis. It is hypothesized that they also modulate inflammation. The aim of this study was to examine whether lovastatin inhibits macrophage inflammatory processes and clarify its mechanism of action. Methods and Results-We examined the effects of statins on phagocytosis of antibody-coated red blood cells by cultured human monocytes and mouse peritoneal macrophages. Lovastatin, simvastatin, and zaragozic acid, a squalene synthase inhibitor, blocked Fc receptor-mediated phagocytosis by cultured human monocytes and mouse peritoneal macrophages. The inhibitory effect of lovastatin on Fc receptor-mediated phagocytosis was prevented completely by addition of mevalonate, farnesyl pyrophosphate, LDL, or cholesterol to the culture medium. The inhibitory effect of zaragozic acid was reversed by addition of LDL, but not by the addition of geranylgeranyl pyrophosphate, to the medium. In addition, the effect of lovastatin on phagocytosis is a function of cell activation because treatment of cells with tumor necrosis factor-␣ or lipopolysaccharide prevented inhibition of phagocytosis by lovastatin. Conclusions-The inhibition of Fc receptor-mediated phagocytosis of lovastatin is related to its effect on cholesterol biosynthesis rather than its effect on the formation of isoprenoids. (Arterioscler Thromb Vasc

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

“…Lovastatin suppressed Fc␥R-mediated phagocytosis in an HMG-CoA reductase-dependent manner, confirming recent reports (53,54). Interestingly, these authors all concluded that statins suppress Fc␥R-mediated phagocytosis by inhibiting cholesterol biosynthesis, and not by inhibiting prenylation (53,54).…”

“…Mevalonate reversed the ability of lovastatin to potentiate efferocytosis, confirming HMG-CoA reductase dependency. In contrast, lovastatin suppressed phagocytosis of IgG-opsonized erythrocytes through the Fc␥R, as has recently been shown (53,54), and this also appeared to be dependent on HMG-CoA reductase (Fig. 1F).…”

“…Interestingly, these authors all concluded that statins suppress Fc␥R-mediated phagocytosis by inhibiting cholesterol biosynthesis, and not by inhibiting prenylation (53,54). Like efferocytosis, prenylated proteins like Rac-1, Cdc42, and Rab11 are required for Fc␥R-mediated phagocytosis (80,81), and a role for RhoA has been suggested (82).…”

Gamma interferon: a central mediator in atherosclerosis

“…The in vitro effects of statins on IFN-g mediated infl ammatory processes associated with plaque progression will be considered (Table 4) to exemplify how statin anti-infl ammatory effects in vivo could occur in part through multiple interventions along the IFN-g axis. Statins have been demonstrated to inhibit both IFN-g production in T cells by shifting the T cell population towards the Th2 pathway [183][184][185] as well as inhibiting IFN-g effects on macrophages, endothelial cells and vascular SMC [186][187][188][189][190][191][192][193][194][195][196][197][198]. In general, the in vitro and in vivo effects of statins on IFN-g stimulated cellular changes were dose dependent and vary in potency depending on the specifi c statin.…”

Vulnerable plaque: Definition, detection, treatment, and future implications

“…Large population studies have demonstrated significant reduction in first acute coronary events with statins compared with placebo [49,50]. Statins have been shown to exert their preventive effects through multiple biologic mechanisms, including, but not limited to, improve- ment of endothelial function [51,52], systemic and focal anti-inflammatory effects [53,54], and reduction of thrombogenicity [54,55].…”