The clearance rate of liposomal drugs from the circulation is determined by the rate and extent of both drug release and uptake of liposomes by cells of the mononuclear phagocyte system (MPS). Intravenously injected liposomes initially come into contact with serum proteins. The interaction of liposomes with serum proteins is thought to play a critical role in the liposome clearance. Therefore, in this review, we focus on the role of serum proteins, so-called opsonins, that enhance the clearance of liposomes, when bound to liposomes. In addition to opsonin-dependent liposome clearance, opsonin-independent liposome clearance is also reviewed. As opposed to the conventional (non-surface modification) liposomes, we briefly address the issue of the accelerated clearance of PEGylated-liposomes (sterically stabilized liposomes, long-circulating liposomes) on repeated injection, a process that has recently been observed. (+info)
Fourteen-member macrolides promote the phosphatidylserine receptor-dependent phagocytosis of apoptotic neutrophils by alveolar macrophages.
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An inflammation of the airway of patients with diffuse panbronchiolitis (DPB), is characterized by dense neutrophil infiltration. Resolution of the inflammation can be achieved by the removal of apoptotic neutrophils by human alveolar macrophages (AM) without liberating neutrophil proteases in the airway. To understand clinical efficacy for the treatment of DPB by 14- or 15-member macrolides, their effects on the phagocytosis of apoptotic neutrophils by AM were examined. Treatment of AM with erythromycin (ERY) or clarithromycin at clinically achievable levels significantly increased the levels of phagocytosis of apoptotic neutrophils. A serum factor was not essential for the enhancement by these 14-member macrolides. Of the antibiotics tested, these effects were specific for the 14-member macrolides and a 15-member macrolide, azithromycin, but not for the 16-member macrolides, clindamycin or beta-lactam antibiotics. The enhanced phagocytosis of apoptotic neutrophils by ERY had no effect on the levels of interleukin-8 or tumor necrosis factor alpha production by lipopolysaccharide-stimulated AM after phagocytosis of the apoptotic neutrophils. The increased phagocytosis of apoptotic neutrophils by ERY was also found to be phosphatidylserine receptor-dependent for AM. These data indicate a novel anti-inflammatory action of 14-member and 15-member macrolides, and suggest that such antibiotics achieve clinical efficacy for patients with DPB, in part, through enhancing the nonphlogistic phagocytosis of apoptotic neutrophils by AM. (+info)
Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9.
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PLU-1 is a large (1544 amino acids) nuclear protein that is highly expressed in breast cancers and is proposed to function as a regulator of gene expression. A yeast two-hybrid screen using PLU-1 as bait has identified two unrelated PLU-1 interacting proteins, namely brain factor-1 (BF-1) and paired box 9 (PAX9), both of which are developmental transcription factors. BF-1 and PAX9 interact with PLU-1 via a novel conserved sequence motif (Ala-X-Ala-Ala-X-Val-Pro-X4-Val-Pro-X8-Pro, termed the VP motif), because deletion or site-directed mutagenesis of this motif in either protein abolishes PLU-1 interaction in vivo. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression. Mutation of the PLU-1 binding motifs in BF-1 and PAX9 abolishes the observed PLU-1 co-repression activity. These data support a role for PLU-1 acting as a transcriptional co-repressor of two unrelated developmental transcription factors. Because both BF-1 and PAX proteins interact with members of the groucho co-repressor family, it is plausible that PLU-1 has a role in groucho-mediated transcriptional repression. (+info)
Annexin I is an endogenous ligand that mediates apoptotic cell engulfment.
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Engulfment of apoptotic cells requires presentation of new cell surface ligands by the dying cells. Using a differential proteomics technology, we identify that annexin I is a caspase-dependent engulfment ligand; it is recruited from the cytosol and exported to the outer plasma membrane leaflet, colocalizes with phosphatidylserine, and is required for efficient clearance of apoptotic cells. Furthermore, phosphatidylserine receptor (PSR) clustering around apoptotic cells indicates a requirement for annexin I. In the nematode Caenorhabditis elegans, downregulation of the annexin homolog prevents efficient engulfment of pharyngeal cell corpses. These results provide novel mechanistic insights into how apoptotic cells are removed and may explain a pathogenic mechanism of chronic inflammatory diseases where annexin I autoantibodies have been described. (+info)
Rapid, noninflammatory and PS-dependent phagocytic clearance of necrotic cells.
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In pathological situations, different modes of cell death are observed, and information on the role and uptake of nonapoptotic corpses is scarce. Here, we modeled two distinct forms of death in human Jurkat T cells treated with staurosporine: classical apoptosis under normal culture conditions and programmed death with necrotic morphology under ATP-depleting conditions (necPCD). When offered to phagocytes, both types of cell corpses (but not heat-killed unscheduled necrotic cells) reduced the release of the proinflammatory cytokine TNF from the macrophages. The necPCD cells were efficiently engulfed by macrophages and microglia, and from mixtures of necPCD and apoptotic cells macrophages preferentially engulfed the necrotic cells. Using a newly developed assay, we demonstrated that phosphatidylserine is translocated to the surface of such necrotic cells. We demonstrate that this can occur independently of calcium signals, and that surface phosphatidylserine is essential for the uptake of necrotic cells by both human macrophages and murine microglia. (+info)
Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12.
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During apoptosis, phosphatidylserine, which is normally restricted to the inner leaflet of the plasma membrane, is exposed on the surface of apoptotic cells and has been suggested to act as an "eat-me" signal to trigger phagocytosis. It is unclear how phagocytes recognize phosphatidylserine. Recently, a putative phosphatidylserine receptor (PSR) was identified and proposed to mediate recognition of phosphatidylserine and phagocytosis. We report that psr-1, the Caenorhabditis elegans homolog of PSR, is important for cell corpse engulfment. In vitro PSR-1 binds preferentially phosphatidylserine or cells with exposed phosphatidylserine. In C. elegans, PSR-1 acts in the same cell corpse engulfment pathway mediated by intracellular signaling molecules CED-2 (homologous to the human CrkII protein), CED-5 (DOCK180), CED-10 (Rac GTPase), and CED-12 (ELMO), possibly through direct interaction with CED-5 and CED-12. Our findings suggest that PSR-1 is likely an upstream receptor for the signaling pathway containing CED-2, CED-5, CED-10, and CED-12 proteins and plays an important role in recognizing phosphatidylserine during phagocytosis. (+info)
Phosphatidylserine receptor cooperates with high-density lipoprotein receptor in recognition of apoptotic cells by thymic nurse cells.
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The thymus contains many apoptotic cells that arise from the process of positive and negative selection. Both thymic macrophages and thymic nurse cells/nursing thymic epithelial cells (nursing TECs), non-professional phagocytes, recognize and ingest apoptotic cells without inflammation or tissue damage. Previously we reported that human scavenger receptor class B (SR-B1) is involved in recognition of apoptotic thymocytes by nursing TECs. In this study, we examined the expression and role of a phosphatidylserine receptor (PSR). This receptor is believed to participate in the clearance of apoptotic cells. PSR was strongly expressed in nursing TECs. Transforming growth factor-beta augmented the expression of PSR leading to enhanced binding of apoptotic cells to nursing TECs. In nursing TECs, suppressed expression of human SR-B1 with anti-PSR antibody decreased binding of apoptotic thymocytes to nursing TECs. Our results suggest that both PSR and SR-B1 are expressed in nursing TECs and these receptors appear to play a major role in the clearance of apoptotic cells from the thymus. (+info)
The phosphatidylserine receptor from Hydra is a nuclear protein with potential Fe(II) dependent oxygenase activity.
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BACKGROUND: Apoptotic cell death plays an essential part in embryogenesis, development and maintenance of tissue homeostasis in metazoan animals. The culmination of apoptosis in vivo is the phagocytosis of cellular corpses. One morphological characteristic of cells undergoing apoptosis is loss of plasma membrane phospholipid asymmetry and exposure of phosphatidylserine on the outer leaflet. Surface exposure of phosphatidylserine is recognised by a specific receptor (phosphatidylserine receptor, PSR) and is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. RESULTS: We have cloned the PSR receptor from Hydra in order to investigate its function in this early metazoan. Bioinformatic analysis of the Hydra PSR protein structure revealed the presence of three nuclear localisation signals, an AT-hook like DNA binding motif and a putative 2-oxoglutarate (2OG)-and Fe(II)-dependent oxygenase activity. All of these features are conserved from human PSR to Hydra PSR. Expression of GFP tagged Hydra PSR in hydra cells revealed clear nuclear localisation. Deletion of one of the three NLS sequences strongly diminished nuclear localisation of the protein. Membrane localisation was never detected. CONCLUSIONS: Our results suggest that Hydra PSR is a nuclear 2-oxoglutarate (2OG)-and Fe(II)-dependent oxygenase. This is in contrast with the proposed function of Hydra PSR as a cell surface receptor involved in the recognition of apoptotic cells displaying phosphatidylserine on their surface. The conservation of the protein from Hydra to human infers that our results also apply to PSR from higher animals. (+info)