Vitronectin Receptor-Mediated Phagocytosis of Cells Undergoing Apoptosis

Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Nature (Impact Factor: 41.46). 02/1990; 343(6254):170-3. DOI: 10.1038/343170a0
Source: PubMed


Phagocyte recognition of cells that have undergone apoptosis (programmed cell death) is an event of broad biological significance. Characterized by endogenous endonuclease activation, which results in chromatin fragmentation and nuclear condensation, apoptosis leads to swift ingestion of intact but 'senescent' or 'unwanted' cells by phagocytes in processes as diverse as the physiological involution of organs, the remodelling of embryonic tissues, and metamorphosis. The cell-surface mechanisms by which macrophages recognize apoptotic cells as 'senescent-self' have remained obscure. Here we report that macrophage recognition of apoptotic cells (both neutrophils and lymphocytes) is mediated by the vitronectin receptor, a heterodimer belonging to the beta 3 or cytoadhesin family of the integrins. Previously, the functions of the vitronectin receptor were believed to be limited to cell anchorage, but our findings indicate that the receptor has a novel and direct role in self-senescent-self intercellular recognition leading to macrophage phagocytosis of cells undergoing apoptosis.

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    • "Myofibroblasts also express αvβ3 integrins and can be targeted with a pro-collagen-targeting Cy5.5-RGD imaging peptide [36]. In addition to neovessels and myofibroblasts, macrophages have also been shown to express αvβ3 integrin [37]. However, the relative amounts of integrin in these cell types have not been compared over time in MI. "
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    ABSTRACT: Background Expression of αvβ3 integrin is increased after myocardial infarction as part of the repair process. Increased expression of αvβ3 has been shown by molecular imaging with 18F-galacto-RGD in a rat model. The 68Ga-labelled RGD compounds 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 have high specificity and affinity, and may therefore serve as alternatives of 18F-galacto-RGD for integrin imaging. Methods Left coronary artery ligation was performed in rats. After 1 week, rats were imaged with [13N]NH3, followed by 18F-galacto-RGD, 68Ga-NODAGA-RGD or 68Ga-TRAP(RGD)3 using a dedicated animal PET/CT device. Rats were killed, and the activity in tissues was measured by gamma counting. The heart was sectioned for autoradiography and histology. Immunohistochemistry was performed on consecutive sections using CD31 for the endothelial cells and CD61 for β3 expression (as part of the αvβ3 receptor). Results In vivo imaging showed focal RGD uptake in the hypoperfused area of infarcted myocardium as defined with [13N]NH3 scan. In autoradiography images, augmented uptake of all RGD tracers was observed within the infarct area as verified by the HE staining. The tracer uptake ratios (infarct vs. remote) were 4.7 ± 0.8 for 18F-galacto-RGD, 5.2 ± 0.8 for 68Ga-NODAGA-RGD, and 4.1 ± 0.7 for 68Ga-TRAP(RGD)3. The 68Ga-NODAGA-RGD ratio was higher compared to 68Ga-TRAP(RGD)3 (p = 0.04), but neither of the 68Ga tracers differed from 18F-galacto-RGD (p > 0.05). The area of augmented 68Ga-RGD uptake was associated with β3 integrin expression (CD61). Conclusion 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 uptake was equally increased in the infarct area at 1 week post infarction as 18F-galacto-RGD. These results show the potential of 68Ga-labelled RGD peptides to monitor integrin expression as a part of myocardial repair and angiogenesis after ischaemic injury in vivo.
    Full-text · Article · May 2013 · EJNMMI Research
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    • "Various studies in macrophages60,61 have elucidated the means utilized in the recognition and engulfment of apoptotic cells. These include an uncharacterized lectin-dependent interaction;62 a charge-sensitive process involving the CD36/vitronectin receptor complex interacting with unknown moieties on apoptotic neutrophils’ surfaces via a thrombospondin bridge;63,64 a stereo specific recognition of phosphatidylserine (PS) that is exposed on the surface of the apoptotic cell after loss of membrane asymmetry,65,66 redistribution of PS on the phagocyte,67 macrophage scavenger receptors,68,69 CD14,70,71 CD68,72 ABC1 transporter,73 Dock180, beta-1-integrins,74 CD4475 and opsinization by MFG-E8, C1q, Mannonse binding lectin (MBL) and E6 (reviewed in Elliott and Ravichandran).76 It is been known for many years that a number of non-professional phagocytes, including dendritic cells, lung fibroblasts, and smooth muscle cells, also have the capacity to recognize and ingest apoptotic cells.77 "
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    ABSTRACT: Asthma is an increasingly common respiratory condition characterized by reversible airway obstruction, bronchial hyper-responsiveness and airway inflammation with a clear unmet need for more effective therapy. Eosinophilic asthma is a phenotype of the condition that features increased blood or sputum eosinophils whose numbers correlate with disease severity. Several lines of evidence are now emerging, which implicate increased persistence of eosinophils in the lungs of patients with asthma as a consequence of inhibition of and defects in the apoptotic process, together with impaired apoptotic cell removal mechanisms. This article will update our knowledge of the mechanisms controlling eosinophil apoptosis and clearance, together with evidence implicating defects in apoptosis and pro-inflammatory cell removal in asthma. Recent developments in novel therapies for asthma that target eosinophil apoptotic and/or clearance pathways will also be discussed.
    Preview · Article · Apr 2013 · Journal of Cell Death
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    • "This lipid, normally concentrated on the inner leaflet of the plasma membrane, loses its asymmetric distribution during apoptosis and is translocated to the outer leaflet of the plasma membrane [13], [15]. Phagocyte recognition of PS is mediated directly via one or more PS receptors, including BAI-1, Tim-4 and Stabilin-2 [16]–[21], or by bridging molecules, that bind PS on the apoptotic cell and a receptor on the phagocyte [22]–[24]. For some of these receptors direct or indirect ligation to PS results in Rac-dependent cytoskeletal reorganization, which ultimately leads to engulfment of the apoptotic cell [12]. "
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    ABSTRACT: Defective clearance of apoptotic cells has emerged as an important contributing factor to the pathogenesis of many diseases. Although many efforts have been made to understand the machinery involved in the recognition between phagocytes and potential targets, little is known about the intracellular transport of phagosomes containing apoptotic cells within mammalian cells. We have, therefore, performed a detailed study on the maturation of phagosomes containing apoptotic cells in a non-professional phagocytic cell line. This process was compared with the maturation of IgG-opsonized particles, which are internalized via the Fcγ-receptor (Fcγ-R), one of the best characterized phagocytic receptor, in the same cell line stably expressing the Fcγ-RIIA. By comparing markers from different stages of phagosome maturation, we have found that phagosomes carrying apoptotic particles reach the lysosomes with a delay compared to those containing IgG-opsonized particles. Enrichment of the apoptotic particles in phosphatidylserine (PS) neither changed the kinetics of their engulfment nor the maturation process of the phagosome.
    Full-text · Article · Oct 2012 · PLoS ONE
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