Beta-2-glycoprotein 1-dependent macrophage uptake of apoptotic cells. Binding to lipoprotein receptor-related protein receptor family members.
ABSTRACT The recognition and removal of apoptotic cells is critical to development, tissue homeostasis, and the resolution of inflammation. Many studies have shown that phagocytosis is regulated by signaling mechanisms that involve distinct ligand-receptor interactions that drive the engulfment of apoptotic cells. Studies from our laboratory have shown that the plasma protein beta-2-glycoprotein 1 (beta2GP1), a member of the short consensus repeat superfamily, binds phosphatidylserine-containing vesicles and apoptotic cells and promotes their bridging and subsequent engulfment by phagocytes. The phagocyte receptor for the protein/apoptotic cell complex, however, is unknown. Here we report that a member of the low density lipoprotein receptor-related protein family on phagocytes binds and facilitates engulfment of beta2GP1-phosphatidylserine and beta2GP1-apoptotic cell complexes. Using recombinant beta2GP1, we also show that beta2GP1-dependent uptake is mediated by bridging of the target cell to the phagocyte through the protein C- and N-terminal domains, respectively.
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ABSTRACT: In normal healthy cells phosphatidylserine is located in the inner leaflet of the plasma membrane. However, on activated platelets, dying cells and under specific circumstances also on various types of viable leukocytes phosphatidylserine is actively externalized to the outer leaflet of the plasma membrane. Annexin A5 has the ability to bind in a calcium-dependent manner to phosphatidylserine and to form a membrane-bound two-dimensional crystal lattice. Based on these abilities various functions for extracellular annexin A5 on the phosphatidylserine-expressing plasma membrane have been proposed. In this review we describe possible mechanisms for externalization of annexin A5 and various processes in which extracellular annexin A5 may play a role such as blood coagulation, apoptosis, phagocytosis and formation of plasma membrane-derived microparticles. We further highlight the recent discovery of internalization of extracellular annexin A5 by phosphatidylserine-expressing cells.Biochimica et Biophysica Acta 07/2008; 1783(6):953-63. DOI:10.1016/j.bbamcr.2008.01.030 · 4.66 Impact Factor
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ABSTRACT: Oxidized low-density lipoprotein (oxLDL) promotes atherosclerosis through a complex interaction of inflammatory and immunologic factors that lead to macrophage lipid uptake and foam cell formation. OxLDL interacts with beta2-glycoprotein I (beta2GPI) forming oxLDL/beta2GPI complexes. These complexes may be formed in the arterial intima during atherogenesis and released into the circulation. Autoantibodies against oxLDL/beta2GPI complexes have been demonstrated in patients with systemic lupus erythematosus and/or antiphospholipid syndrome, and shown to be significantly associated with arterial thrombosis. The observation that monoclonal autoantibodies against oxLDL/beta2GPI complexes significantly increased the oxLDL uptake by macrophages strongly suggests that such IgG autoantibodies are pro-atherogenic. In this article, we review the recent progress in our understanding of LDL oxidation, oxLDL/beta2GPI complex formation, and immune regulation of atherogenesis.Clinical Reviews in Allergy & Immunology 12/2008; 37(1):12-9. DOI:10.1007/s12016-008-8096-8 · 4.73 Impact Factor
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ABSTRACT: Glatiramer acetate (GA, Copaxone) has beneficial effects on the clinical course of relapsing-remitting multiple sclerosis (RRMS). However, the exact molecular mechanisms of GA effects are only partially understood. To characterized GA molecular effects in RRMS patients within 3 months of treatment by microarray profiling of peripheral blood mononuclear cells (PBMC). Gene-expression profiles were determined in RRMS patients before and at 3 months after initiation of GA treatment using Affimetrix (U133A-2) microarrays containing 14,500 well-characterized human genes. Most informative genes (MIGs) of GA-induced biological convergent pathways operating in RRMS were constructed using gene functional annotation, enrichment analysis and pathway reconstruction bioinformatic softwares. Verification at the mRNA and protein level was performed by qRT-PCR and FACS. GA induced a specific gene expression molecular signature that included altered expression of 480 genes within 3 months of treatment; 262 genes were up-regulated, and 218 genes were down-regulated. The main convergent mechanisms of GA effects were related to antigen-activated apoptosis, inflammation, adhesion, and MHC class-I antigen presentation. Our findings demonstrate that GA treatment induces alternations of immunomodulatory gene expression patterns that are important for suppression of disease activity already at three months of treatment and can be used as molecular markers of GA activity.Disease markers 11/2009; 27(2):63-73. DOI:10.3233/DMA-2009-0651 · 2.17 Impact Factor