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 β-2-glycoprotein
1 (β2GP1), 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 β2GP1-phosphatidylserine and β2GP1-apoptotic cell complexes. Using recombinant
β2GP1, we also show that β2GP1-dependent uptake is mediated by bridging of the target cell to the phagocyte through the protein
C- and N-terminal domains, respectively.
"Given that none of the surface expression of these receptors were upregulated by HIV-1 infection in MDMs, we focused on receptors of phosphatidylserine-binding ligands, such as CD91/LRP-1. CD91/LRP-1 binds β2-glycoprotein, which has been reported to interact with phosphatidylserines of apoptotic bodies . Our findings that surface CD91/LRP-1 is increased in MDMs treated with Tat, as well as following HIV-1 infection, suggested, at first, that this entry pathway is involved in enhanced amastigote uptake by macrophages. "
[Show abstract][Hide abstract] ABSTRACT: Over the past decade, the number of reported human immunodeficiency virus type-1 (HIV-1)/Leishmania co-infections has risen dramatically, particularly in regions where both diseases are endemic. Although it is known that HIV-1 infection leads to an increase in susceptibility to Leishmania infection and leishmaniasis relapse, little remains known on how HIV-1 contributes to Leishmania parasitaemia. Both pathogens infect human macrophages, and the intracellular growth of Leishmania is increased by HIV-1 in co-infected cultures. We now report that uninfected bystander cells, not macrophages productively infected with HIV-1, account for enhanced phagocytosis and higher multiplication of Leishmania parasites. This effect can be driven by HIV-1 Tat protein and transforming growth factor-beta (TGF-β). Furthermore, we show for the first time that HIV-1 infection increases surface expression of phosphatidylserine receptor CD91/LRP-1 on human macrophages, thereby leading to a Leishmania uptake by uninfected bystander cells in HIV-1-infected macrophage populations. The more important internalization of parasites is due to interactions between the scavenger receptor CD91/LRP-1 and phosphatidylserine residues exposed at the surface of Leishmania. We determined also that enhanced CD91/LRP-1 surface expression occurs rapidly following HIV-1 infection, and is triggered by the activation of extracellular TGF-β. Thus, these results establish an intricate link between HIV-1 infection, Tat, surface CD91/LRP-1, TGF-β, and enhanced Leishmania phosphatidylserine-mediated phagocytosis.
PLoS ONE 03/2012; 7(3):e32761. DOI:10.1371/journal.pone.0032761 · 3.23 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.