Abstract 5071: Suppression of Macrophage Recruitment, Foam Cell Formation and Atherogenesis by the Negative Regulator of Cytokine Signaling SOCS-1
Introduction: Inflammation is the hallmark of atherosclerosis leading to myocardial infarction, sudden cardiac death or stroke. While pro-inflammatory signaling pathways have been studied extensively, the impact of negative regulators of cytokine signalling i.e. suppressor of cytokine signaling (SOCS)-1 remains unclear. We postulated that a systemic SOCS-1 deficiency (socs-1−/−) in the atherosclerosis prone low density lipoprotein receptor (ldlr−/−) mouse results in a pre-mature, aggravated atherogenesis.
Methods and Results: Since systemic deletion of SOCS-1 is lethal within 3 weeks post partum due to a systemic inflammation mainly caused by uncontrolled signalling of interferon-γ (IFNG), we used mice lacking mature lymphocytes (rag2−/−), the major source for interferon-γ. Thus, socs-1−/−, rag2−/− mice were crossed with ldlr−/− mice and fed a high-cholesterol western diet for 30 days. Even though serum lipid levels did not differ between the groups, triple-KO mice (socs-1−/−, rag2−/−, ldlr−/−) showed enhanced atherosclerotic plaque formation (en face: oil red O staining/aortic root: oil red O staining, N=8 –15 animals/group, P<0.05) that was mainly due to enhanced accumulation of macrophages (aortic root: MOMA-2 immunohistochemistry, N=6 –15 animals/group, P<0.05). In-vitro, socs-1−/− bone-marrow derived macrophages (BMDM) exhibited increased migration towards CCL-2 associated with enhanced secretion of CCL-2 (transwell assay, ELISA, N=8, P<0.05). Furthermore, socs-1−/− BMDM showed enhanced foam cell formation when stimulated with oxidized(ox)LDL (oil red O staining, N=8, P<0.05).
Summary and Conclusion: SOCS-1 deficiency combined with a pro-atherogenic background results in increased atherosclerotic plaque formation. The underlying mechanism involves an enhanced oxLDL uptake and migration capacity of socs-1−/− macrophages as well as enforced recruitment of inflammatory cells by increased secretion of CCL-2. Thus, SOCS-1 seems to represent a molecular brake controlling macrophage recruitment and foam cell formation in atherogenesis and thereby may evolve as a suitable target for future therapeutic strategies.