Inhibition of foam cell formation using a soluble CD68-Fc fusion protein

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 88; no. 9; pp. 909 - 920
• Main Authors: Daub, Karin, Siegel-Axel, Dorothea, Schönberger, Tanja, Leder, Christoph, Seizer, Peter, Müller, Karin, Schaller, Martin, Penz, Sandra, Menzel, Dagmar, Büchele, Berthold, Bültmann, Andreas, Münch, Götz, Lindemann, Stephan, Simmet, Thomas, Gawaz, Meinrad
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.09.2010; Springer Nature B.V
• Subjects: Animals; Antigens, CD - chemistry; Antigens, CD - genetics; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - chemistry; Antigens, Differentiation, Myelomonocytic - genetics; Antigens, Differentiation, Myelomonocytic - metabolism; Apolipoproteins E - metabolism; Biomedical and Life Sciences; Biomedicine; CHO Cells; Cricetinae; Cricetulus; Foam Cells - cytology; Foam Cells - metabolism; Human Genetics; Humans; Immunoglobulin Fc Fragments - chemistry; Immunoglobulin Fc Fragments - genetics; Internal Medicine; Lipoproteins, LDL - metabolism; Macrophages - metabolism; Mice; Molecular Medicine; Original Article; Plaque, Atherosclerotic - metabolism; Receptors, Scavenger - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Surface Plasmon Resonance; Transfection; Lipoproteins; Platelets; Macrophages; Foam cells; Atherosclerosis
• ISSN: 0946-2716; 1432-1440; 1432-1440
• DOI: 10.1007/s00109-010-0629-y

The appearance of lipid-rich foam cells is a major feature of vulnerable atherosclerotic plaque formation. The transformation of macrophages into foam cells results from excessive uptake of cholesterol-rich particles by scavenger receptors such as CD68. We cloned a CD68-Fc immunoadhesin, a fusion protein consisting of the extracellular domain of the human CD68 and a human Fc domain, and investigated the function in vitro. Specific binding of CD68-Fc to OxLDL with an affinity of 10 nmol/L was determined by surface plasmon resonance and increased binding to lipid-rich human and ApoE −/− mice plaque tissue. This was confirmed both by immunohistochemical staining of CD68-Fc-treated paraffin sections from human plaques and by ELISA-based quantification of CD68-Fc binding to human atherosclerotic plaque extracts. In an in vitro model of macrophage/foam cell formation, CD68-Fc reduced foam cell formation significantly. This was caused both by interference of CD68-Fc with OxLDL uptake into macrophages and platelets and by the inhibition of platelet/OxLDL phagocytosis. Finally, expression of metalloproteinases by macrophages/foam cells was inhibited by CD68-Fc. In conclusion, CD68-Fc seems to be a promising new tool for preventing macrophage/foam cell formation. Thus, CD68-Fc might offer a novel therapeutic strategy for patients with acute coronary syndrome by modulating the generation of vulnerable plaques.