Engulfment of apoptotic cells: signals for a good meal

Ravichandran, Kodi S.; Lorenz, Ulrike

doi:10.1038/nri2214

Cited by 579 publications

(596 citation statements)

References 118 publications

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“…It occurs without compromising the barrier function of the cell membrane allowing already on a short time scale after the apoptotic stimulus to change the cell-to-cell recognition. Together with externalization of several protein factors the exposed PS molecules generate an 'eat-me' signal that allows the clearance of apoptotic cells by phagocytes (Erwig and Henson 2008;Ravichandran and Lorenz 2007).…”

Section: Aminophospholipid Asymmetry Of Plasma Membrane and Its Apoptmentioning

confidence: 99%

“…Anionic lipids expressed on activated platelets are important for the coordinated assembly of coagulation factors (Kerbiriou-Nabias and GeldwerthFeniger 2007). Activated macrophages that are engaged to engulf dying cells also expose PS on their surface, and inhibition of their PS exposure greatly impairs phagocytic capacity (Ravichandran and Lorenz 2007). Thus the methods detecting PS externalization lack absolute specificity for apoptosis and they can be used also in the studies of these processes (Elliott et al 2005).…”

Section: Aminophospholipid Asymmetry Of Plasma Membrane and Its Apoptmentioning

confidence: 99%

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Beyond annexin V: fluorescence response of cellular membranes to apoptosis

2012

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Dramatic changes in the structure of cell membranes on apoptosis allow easy, sensitive and non-destructive analysis of this process with the application of fluorescence methods. The strong plasma membrane asymmetry is present in living cells, and its loss on apoptosis is commonly detected with the probes interacting strongly and specifically with phosphatidylserine (PS). This phospholipid becomes exposed to the cell surface, and the application of annexin V labeled with fluorescent dye is presently the most popular tool for its detection. Several methods have been suggested recently that offer important advantages over annexin V assay with the ability to study apoptosis by spectroscopy of cell suspensions, flow cytometry and confocal or twophoton microscopy. The PS exposure marks the integrated changes in the outer leaflet of cell membrane that involve electrostatic potential and hydration, and the attempts are being made to provide direct probing of these changes. This review describes the basic mechanisms underlying the loss of membrane asymmetry during apoptosis and discusses, in comparison with the annexin V-binding assay, the novel fluorescence techniques of detecting apoptosis on cellular membrane level. In more detail we describe the detection method based on smart fluorescent dye F2N12S incorporated into outer leaflet of cell membrane and reporting on apoptotic cell transformation by easily detectable change of the spectral distribution of fluorescent emission. It can be adapted to any assay format.

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Section: Aminophospholipid Asymmetry Of Plasma Membrane and Its Apoptmentioning

confidence: 99%

Section: Aminophospholipid Asymmetry Of Plasma Membrane and Its Apoptmentioning

confidence: 99%

Beyond annexin V: fluorescence response of cellular membranes to apoptosis

2012

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“…The search for macrophage receptors responsible for the recognition and clearance of apoptotic cells has focused on molecules which recognize and bind phosphatidylserine (PS) since exposure of this "eat-me" signal on the surface of apoptotic cells is the signal for their removal by professional or non-professional phagocytes [4]. A family of Type-1 single transmembrane proteins, T-cell immunoglobulin, and mucin-domain containing molecules (Tim-1 and Tim-4) have been identified as PS receptors and shown to be important for the binding and engulfment of apoptotic cells by macrophages [13][14][15].…”

Section: Macrophage Scavenger Receptorsmentioning

confidence: 99%

“…In vertebrates, phagocytosis acts as an immediate innate immune response to invasion by bacteria thereby clearing or limiting the bacterial load until an adaptive immune response can be mounted [3]. Phagocytosis is also a critical physiological process for tissue remodeling which removes apoptotic or aged cells in a regulated manner in the absence of inflammation [4]. Specific recognition of the apoptotic cell by the phagocyte occurs without regard to the species or tissue origin of the target or the nature of the apoptotic stimulus and can occur without the involvement of soluble factors [5].…”

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confidence: 99%

A new role for the P2X7 receptor: a scavenger receptor for bacteria and apoptotic cells in the absence of serum and extracellular ATP

Wiley

2012

Purinergic Signalling

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The P2X7 receptor is widely recognized to mediate the proinflammatory effects of extracellular ATP. However this receptor in the absence of ATP may have a function unrelated to inflammation. Our data show that P2X7 expressed on the surface of monocyte/macrophages or on epithelial HEK-293 cells greatly augments the engulfment of latex beads and live and heat-killed bacteria by effector phagocyte in the absence of ATP and serum. The expression of P2X7 on the effector also confers the ability to phagocytose apoptotic target cells and an accumulation of P2X7 can be seen at the attachment point to the target. Activation of the P2X7 receptor by ATP causes a slow dissociation (over 10-15 min) of nonmuscle myosin from the P2X7 membrane complex and abolishes further P2X7-mediated phagocytosis of these targets. The recent crystal structure of the homologous zebrafish P2X4 receptor shows an exposed "nose" of the ectodomain (residues 115-162) which contains three of the five disulfide bonds conserved in all P2X receptors. Three short biotin-labeled peptides mimicking sequence of this exposed region bound to apoptotic target cells but not to either viable cells or to other target particles. All three peptides contained one or two cysteine residues and their replacement by alanine abolished peptide binding. These data implicate thiol-disulfide exchange reactions in the initial tethering of apoptotic cells to macrophage and establish P2X7 as one of the scavenger receptors involved in the recognition and removal of apoptotic cells in the absence of extracellular ATP and serum.

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“…Given that accumulation of apoptotic cells is a cause of glomerulonephritis [19,20], we examined the possibility that OSMdeficient mice develop glomerulonephritis. Interestingly, aged OSMdeficient mice spontaneously produced autoantibodies against dsDNA.…”

Section: Development Of Glomerulonephritis In Aged Osm-deficient Micementioning

confidence: 99%

Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis

et al. 2009

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Oncostatin M (OSM) has been implicated in immune regulation, though its precise role remains elusive. Here we show that OSM plays a crucial role in the prevention of autoimmune diseases. OSM-deficient mice showed normal development of T cells, B cells and DC; however, their thymus showed hypoplasia and altered medullary structure. Autoantibodies against dsDNA accumulated and glomerulonephritis developed in aged OSMdeficient mice. Apoptotic cells accumulated in the thymus of OSM-deficient mice, and the administration of dexamethasone in young OSM-deficient mice resulted in the massive accumulation of apoptotic thymocytes and production of autoantibodies. These results suggest that OSM plays a key role in the prevention of autoimmune disease by regulating the clearance of apoptotic thymocytes.Key words: Apoptosis . Autoimmunity . Phagocytosis Supporting Information available online IntroductionOncostatin M (OSM) is a member of the IL-6 family of cytokines, and the OSM receptor (OSMR) consists of gp130 and the OSMRb subunit [1]. OSM is produced by a variety of cells including hematopoietic cells and fibroblasts, and is involved in various biological systems [2]. We showed previously that the lack of OSM signaling causes altered bone marrow microenvironment [3,4]. As OSM is also produced by Th1 cells and DC [5][6][7][8], OSM is suggested to play a role in immune reactions. In fact, OSM from activated DC regulates CCL21 expression in microvascular endothelial cells and promotes the trafficking of DC to LN [8].Moreover, Tg mice that express OSM using the lck proximal promoter exhibit thymic hypertrophy [9,10], suggesting that OSM may play a role in T-cell development within the thymic environment.Apoptosis is an essential process for development and homeostasis and defective clearance of apoptotic cells can lead to production of autoantibody by releasing cell debris, breaking peripheral tolerance. Macrophages in various tissues play an essential role in the elimination of apoptotic cells by phagocytosis. A vast majority of thymocytes are depleted by apoptosis during T-cell selections; however, apoptotic cells are barely detected in the thymus, indicating the presence of a mechanism to eliminate apoptotic thymocytes. Dying cells are normally removed rapidly from tissues by phagocytes, without eliciting inflammatory or immune responses. Clearance of apoptotic cells is crucial for prevention of autoimmune diseases [11,12] 1664with impaired macrophage phagocytosis exhibit splenomegaly due to accumulation of massive quantities of apoptotic cells and such defect in humans leads to retinitis pigmentosa [13].Previously, we demonstrated that OSM induces the development of thymic macrophages with strong phagocytic activity from intrathymic progenitors via OSM-responsive thymic epithelial cells (TEC) [14,15]. In this report, we show that OSM deficiency resulted in thymic hypoplasia, defective clearance of apoptotic thymocytes, accumulation of autoantibody and glomerulonephritis. Administration of dexamethasone (Dex) in OSM-defi...

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Engulfment of apoptotic cells: signals for a good meal

Cited by 579 publications

References 118 publications

Beyond annexin V: fluorescence response of cellular membranes to apoptosis

Beyond annexin V: fluorescence response of cellular membranes to apoptosis

A new role for the P2X7 receptor: a scavenger receptor for bacteria and apoptotic cells in the absence of serum and extracellular ATP

Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis

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