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‣ The role of the endocytic and autophagic molecular machineries in the removal of apoptotic cells

Viegas, Michelle
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Tese de Doutorado
Português
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Every day the human body turns over billions of cells ensuring the disposal of unwanted targets that die by apoptosis. The prompt and efficient removal of apoptotic cells by cell line (vascular SMC). The maturation of phagosomes containing dying cells was compared with the processing of phagosomes loaded with IgG-opsonized particles, which are internalized via Fcγ-receptors and are the best characterized phagocytic model. At the present work, we provide evidence that the nature of the cargo modulates the phagocytic response, since phagosomes carrying apoptotic particles reach the lysosomes with a delay when compared to those containing IgG-opsonized particles. Furthermore, for the first time, we have identified some canonical autophagy effectors in phagolysosome formation, suggesting that LC3-Associated Phagocytosis (LAP), a process involved in phagosome maturation, implies more than the phagosomal recruitment of LC3 (Sanjuan et al., 2007). Indeed, experiments performed in bone marrow-derived macrophages from p62-KO mice clearly suggest that p62, despite not being required for LC3 recruitment, is important for phagolysosome biogenesis. In summary, this data will improve our knowledge on the molecular machinery and mechanisms involved in efferocytosis. In the end...

‣ Effects of Acute Cold Stress on Phagocytosis of Apoptotic Cells: The Role of Corticosterone

SESTI-COSTA, Renata; BACCAN, Gyselle Chrystina; CHEDRAOUI-SILVA, Silvana; MANTOVANI, Bernardo
Fonte: KARGER Publicador: KARGER
Tipo: Artigo de Revista Científica
Português
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Background and Aims: Stress can alter many aspects of the immune response, and many studies have been conducted on the effects of stress on inflammatory processes, but little is known about its influence on the resolution of inflammation in tissue homeostasis, which includes the clearance of apoptotic cells by macrophages in a non-phlogistic way. In the present study, we investigated the effect of acute cold stress on the phagocytosis of apoptotic cells by macrophages. Methods: Mice were submitted to acute cold stress (4 degrees C for 4 h) and the capacity of peritoneal macrophages to phagocyte apoptotic thymocytes and to secrete anti-inflammatory cytokines was evaluated. Plasma corticosterone and catecholamine levels were investigated to assess their effect on the phagocytic capacity of macrophages in vitro. Results: We showed that acute cold stress decreases phagocytosis of apoptotic cells at the inflammatory site by lipopolysaccharide-activated macrophages but did not affect resting macrophages. The inhibitory effect on phagocytosis is accompanied by a reduced level of TGF-beta and higher IL-10 secretion. After stress, plasma concentrations of corticosterone increased 6-fold, epinephrine 2-fold and norepinephrine 1.7-fold compared to control mice. In vitro experiments showed that the decrease in phagocytosis after stress could be attributed...

‣ Expansion of CD4(+) CD25(+) Foxp3(+) T cells by bone marrow-derived dendritic cells

MARGUTI, Ivo; YAMAMOTO, Guilherme Lopes; COSTA, Thais Boccia da; RIZZO, Luiz Vicente; MORAES, Luciana Vieira de
Fonte: WILEY-BLACKWELL PUBLISHING, INC Publicador: WILEY-BLACKWELL PUBLISHING, INC
Tipo: Artigo de Revista Científica
Português
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Dendritic cells (DCs) are the most important antigen-presenting cells of the immune system and have a crucial role in T-lymphocyte activation and adaptive immunity initiation. However, DCs have also been implicated in maintaining immunological tolerance. In this study, we evaluated changes in the CD4(+) CD25(+) Foxp3(+) T-cell population after co-culture of lymph node cells from BALB/c mice with syngeneic bone marrow-derived DCs. Our results showed an increase in CD4(+) CD25(+) Foxp3(+) T cells after co-culture which occurred regardless of the activation state of DCs and the presence of allogeneic apoptotic cells; however, it was greater when DCs were immature and were pulsed with the alloantigen. Interestingly, syngeneic apoptotic thymocytes were not as efficient as allogeneic apoptotic cells in expanding the CD4(+) CD25(+) Foxp3(+) T-cell population. In all experimental settings, DCs produced high amounts of transforming growth factor (TGF)-beta. The presence of allogeneic apoptotic cells induced interleukin (IL)-2 production in immature and mature DC cultures. This cytokine was also detected in the supernatants under all experimental conditions and enhanced when immature DCs were pulsed with the alloantigen. CD4(+) CD25(+) Foxp3(+) T-cell expansion during co-culture of lymph node cells with DCs strongly suggested that the presence of alloantigen enhanced the number of regulatory T cells (Tregs) in vitro. Our data also suggest a role for both TGF-beta and IL-2 in the augmentation of the CD4(+) CD25(+) Foxp3(+) population.; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); National Council for Scientific and Technologic Development (CNPq)

‣ Mitochondrial Swelling and Incipient Outer Membrane Rupture in Preapoptotic and Apoptotic Cells

Sesso, A.; Belizario, J. E.; Marques, M. M.; Higuchi, M. L.; Schumacher, R. I.; Colquhoun, A.; Ito, E.; Kawakami, J.
Fonte: WILEY-BLACKWELL; HOBOKEN Publicador: WILEY-BLACKWELL; HOBOKEN
Tipo: Artigo de Revista Científica
Português
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Outer mitochondrial membrane (OMM) rupture was first noted in isolated mitochondria in which the inner mitochondrial membrane (IMM) had lost its selective permeability. This phenomenon referred to as mitochondrial permeability transition (MPT) refers to a permeabilized inner membrane that originates a large swelling in the mitochondrial matrix, which distends the outer membrane until it ruptures. Here, we have expanded previous electron microscopic observations that in apoptotic cells, OMM rupture is not caused by a membrane stretching promoted by a markedly swollen matrix. It is shown that the widths of the ruptured regions of the OMM vary from 6 to 250 nm. Independent of the perforation size, herniation of the mitochondrial matrix appeared to have resulted in pushing the IMM through the perforation. A large, long focal herniation of the mitochondrial matrix, covered with the IMM, was associated with a rupture of the OMM that was as small as 6 nm. Contextually, the collapse of the selective permeability of the IMM may precede or follow the release of the mitochondrial proteins of the intermembrane space into the cytoplasm. When the MPT is a late event, exit of the intermembrane space proteins to the cytoplasm is unimpeded and occurs through channels that transverse the outer membrane...

‣ Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells

Oka, Kozo; Sawamura, Tatsuya; Kikuta, Ken-ichiro; Itokawa, Shigekazu; Kume, Noriaki; Kita, Toru; Masaki, Tomoh
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 04/08/1998 Português
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Recognition of the exposure of phosphatidylserine (PS) on the outer surface of plasma membrane has been implicated in the phagocytosis of aged/apoptotic cells. Because oxidized low-density lipoprotein (OxLDL) has been reported to block the phagocytosis, here we examined whether lectin-like OxLDL receptor 1 (LOX-1), the OxLDL receptor in endothelial cells, mediates phagocytosis of aged/apoptotic cells by endothelial cells. Cultured bovine aortic endothelial cells (BAE) and Chinese hamster ovary (CHO) cells expressing bovine LOX-1 (BLOX-1-CHO), but not wild-type CHO-K1 cells, bound aged red blood cells (RBC) and apoptotic cells, which were further phagocytosed. The binding of aged RBC and the phagocytosis of apoptotic cells were inhibited by OxLDL, acetyl LDL, and other LOX-1 ligands in both BAE and BLOX-1-CHO. mAb against LOX-1 blocked the binding of aged RBC to BAE, suggesting a role for LOX-1 in the recognition of aged cells. The recombinant soluble LOX-1 inhibited the interactions of aged/apoptotic cells with both BLOX-1-CHO and BAE and distinguished aged RBC from native RBC and apoptotic cells from native cells. PS liposome inhibited these LOX-1-mediated interactions with aged/apoptotic cells, suggesting LOX-1 recognizes PS of the apoptotic cells. PS exposed on the surface of apoptotic cells is known to be procoagulant. Accordingly...

‣ Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: Evidence that oxidation-specific epitopes mediate macrophage recognition

Chang, Mi-Kyung; Bergmark, Claes; Laurila, Aino; Hörkkö, Sohvi; Han, Ki-Hoon; Friedman, Peter; Dennis, Edward A.; Witztum, Joseph L.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 25/05/1999 Português
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Apoptosis is recognized as important for normal cellular homeostasis in multicellular organisms. Although there have been great advances in our knowledge of the molecular events regulating apoptosis, much less is known about the receptors on phagocytes responsible for apoptotic cell recognition and phagocytosis or the ligands on apoptotic cells mediating such recognition. The observations that apoptotic cells are under increased oxidative stress and that oxidized low-density lipoprotein (OxLDL) competes with apoptotic cells for macrophage binding suggested the hypothesis that both OxLDL and apoptotic cells share oxidatively modified moieties on their surfaces that serve as ligands for macrophage recognition. To test this hypothesis, we used murine monoclonal autoantibodies that bind to oxidation-specific epitopes on OxLDL. In particular, antibodies EO6 and EO3 recognize oxidized phospholipids, including 1-palmitoyl 2-(5-oxovaleroyl) phosphatidylcholine (POVPC), and antibodies EO12 and EO14 recognize malondialdehyde-lysine, as in malondialdehyde-LDL. Using FACS analysis, we demonstrated that each of these EO antibodies bound to apoptotic cells but not to normal cells, whereas control IgM antibodies did not. Confocal microscopy demonstrated cell-surface expression of the oxidation-specific epitopes on apoptotic cells. Furthermore...

‣ Murine glomerular mesangial cell uptake of apoptotic cells is inefficient and involves serum-mediated but complement-independent mechanisms

CORTES-HERNANDEZ, J; FOSSATI-JIMACK, L; CARUGATI, A; POTTER, P K; WALPORT, M J; COOK, H T; BOTTO, M
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em /12/2002 Português
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An increased number of apoptotic bodies have been detected in glomeruli of non-nephritic kidneys of C1q-deficient mice. In these mice an in vivo impaired uptake of apoptotic cells by peritoneal macrophages was also demonstrated. Here we investigated whether C1q plays a role in the in vitro clearance of apoptotic cells by glomerular mesangial cells. Phagocytosis was assessed using a novel flow cytometric assay that was validated by immunofluorescence studies. The uptake of apoptotic cells by mesangial cells, measured as percentage of mesangial cells ingesting apoptotic cells, was ∼25%, 10% and 10% for a T cell lymphoma line (RMA), thymocytes and neutrophils, respectively. The uptake reached a plateau phase after 3 h, was specific for apoptotic cells and was mediated by serum but not by complement components C1q or C3. The phagocytosis of apoptotic cells was significantly inhibited by Arg-Gly-Asp-Ser (RGDS), a peptide capable of blocking the interaction of thrombospondin with CD36 or the vitronectin receptor. Pretreatment of the mesangial cells with dexamethasone (200 nm) but not with LPS increased the uptake markedly. These findings indicate that murine mesangial cells are capable of taking up syngeneic apoptotic cells, although much less efficiently than professional phagocytic cells. They also show that serum proteins other than complement components mediate the removal of apoptotic cells by murine mesangial cells in vitro.

‣ Activation-induced CD154 expression abrogates tolerance induced by apoptotic cells*

Gurung, Prajwal; Kucaba, Tamara A.; Ferguson, Thomas A.; Griffith, Thomas S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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The decision to generate a productive immune response or tolerance often depends on the context in which T cells first see Ag. Using a classical system of tolerance induction, we examined the immunological consequence of Ag encountered in the presence of naïve or activated apoptotic cells. Naïve apoptotic cells induced tolerance when injected i.v.; however, previously activated apoptotic cells induced immunity. Further analysis revealed a key role for CD154, as tolerance resulted after i.v. injection of either naïve or activated apoptotic CD154−/− T cells, while co-injection of an agonistic anti-CD40 mAb with naïve apoptotic T cells induced robust immunity. DC fed activated apoptotic T cells in vitro produced IL-12p40 in a CD154-dependent manner, and the use of IL-12p40−/− mice or mAb-mediated neutralization of IL-12 revealed a link between CD154, IL-12, and the ability of activated apoptotic T cells to induce immunity rather than tolerance. Collectively these results show that CD154 expression on apoptotic T cells can determine the outcome of an immune response to Ag recognized within the context of the apoptotic cells, and suggest the balance between naïve and activated apoptotic T cells may dictate whether a productive immune response is encouraged.

‣ Nucleotides released by apoptotic cells act as a find-me signal for phagocytic clearance

Elliott, Michael R.; Chekeni, Faraaz B.; Trampont, Paul C.; Lazarowski, Eduardo R.; Kadl, Alexandra; Walk, Scott F.; Park, Daeho; Woodson, Robin I.; Ostankovich, Marina; Sharma, Poonam; Lysiak, Jeffrey J.; Harden, T. Kendall; Leitinger, Norbert; Ravichand
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 10/09/2009 Português
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Phagocytic removal of apoptotic cells occurs efficiently in vivo such that even in tissues with significant apoptosis, very few apoptotic cells are detectable1. This is thought to be due to the release of find-me signals by apoptotic cells that recruit motile phagocytes such as monocytes, macrophages, and dendritic cells, leading to the prompt clearance of the dying cells2. However, the identity and in vivo relevance of such find-me signals are not well understood. Here, through several lines of evidence, we identify extracellular nucleotides as a critical apoptotic cell find-me signal. We demonstrate the caspase-dependent release of ATP and UTP (in equimolar quantities) during the early stages of apoptosis by primary thymocytes and cell lines. Purified nucleotides at these concentrations were sufficient to induce monocyte recruitment comparable to apoptotic cell supernatants. Enzymatic removal of ATP and UTP (by apyrase or ectopic CD39 expression) abrogated the ability of apoptotic cell supernatants to recruit monocytes in vitro and in vivo. We then identified the ATP/UTP receptor P2Y2 as a critical sensor of nucleotides released by apoptotic cells using RNAi depletion studies in monocytes, and macrophages from P2Y2-null mice3. The in vivo relevance of nucleotides in apoptotic cell clearance was revealed by two approaches. First...

‣ Macrophage Response to Apoptotic Cells Varies with the Apoptotic Trigger and Is Not Altered by a Deficiency in LRP Expression

Kozmar, Ana; Greenlee-Wacker, Mallary C.; Bohlson, Suzanne S.
Fonte: S. Karger AG Publicador: S. Karger AG
Tipo: Artigo de Revista Científica
Português
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Rapid engulfment of apoptotic cells in the absence of inflammation is required for maintenance of normal tissue homeostasis. The low-density lipoprotein receptor-related protein-1 (LRP/CD91) is a receptor mediating interactions between macrophages and apoptotic cells, but recent reports have challenged the requirement of this surface protein in this process. To explore the role of LRP in the recognition of apoptotic cells, target cells were generated with two distinct inducers of apoptotic cell death, etoposide and actinomycin-D. Jurkat T cells rendered apoptotic with etoposide exposed phosphatidylserine (PtdSer) and triggered engulfment by murine bone marrow-derived macrophages (BMDM), however they failed to suppress lipopolysaccharide-driven inflammatory cytokine secretion or, correspondingly, NFκB-dependent or TNFα promoter-driven transcriptional activity in transfected RAW264.7 macrophages. In contrast, induction of apoptosis in either Jurkat cells or HeLa epithelial cells with actinomycin-D resulted in diminution of proinflammatory signaling from RAW264.7 cells and BMDM. Treatment of actinomycin-treated Jurkat cells with Q-VD-OPh, an irreversible inhibitor of caspase activity, blocked apoptosis, as assessed by the inhibition of PtdSer exposure; however...

‣ Two-Step Engulfment of Apoptotic Cells

Toda, Satoshi; Hanayama, Rikinari; Nagata, Shigekazu
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /01/2012 Português
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Apoptotic cells expose phosphatidylserine on their surface as an “eat me” signal, and macrophages respond by engulfing them. Although several molecules that specifically bind phosphatidylserine have been identified, the molecular mechanism that triggers engulfment remains elusive. Here, using a mouse pro-B cell line, Ba/F3, that grows in suspension, we reconstituted the engulfment of apoptotic cells. The parental Ba/F3 cells did not engulf apoptotic cells. Ba/F3 transformants expressing T cell immunoglobulin- and mucin-domain-containing molecule 4 (Tim4), a type I membrane protein that specifically binds phosphatidylserine, efficiently bound apoptotic cells in a phosphatidylserine-dependent manner but did not engulf them. However, Ba/F3 transformants expressing both Tim4 and the integrin αvβ3 complex bound to and engulfed apoptotic cells in the presence of milk fat globule epidermal growth factor factor VIII (MFG-E8), a secreted protein that can bind phosphatidylserine and integrin αvβ3. These results indicate that the engulfment of apoptotic cells proceeds in two steps: Tim4 tethers apoptotic cells, and the integrin αvβ3 complex mediates engulfment in coordination with MFG-E8. A similar two-step engulfment of apoptotic cells was observed with mouse resident peritoneal macrophages. Furthermore...

‣ Anti-phospholipid antibodies (aPL) and apoptosis: prothrombin-dependent aPL as a paradigm for phospholipid-dependent interactions with apoptotic cells☆

Rauch, Joyce; D’Agnillo, Paolo; Subang, Rebecca; Levine, Jerrold S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //2004 Português
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The natural targets of anti-phospholipid antibodies (aPL) and the stimuli that induce them remain unknown. Apoptotic cells have been proposed as both potential targets and immunogens for anti-phospholipid antibodies. Demonstration of selective recognition by anti-phospholipid antibodies provides support for apoptotic cells as antigenic targets. Here, we summarize data showing that prothrombin (PT) binds to apoptotic, but not viable, cells, and that apoptotic-cell bound prothrombin provides a target for human polyclonal and murine monoclonal lupus anticoagulant (LA) antibodies. We discuss findings for two monoclonal lupus anticoagulant antibodies that have high (antibody 29J3-62) or low (antibody 29I4-24) affinity, respectively, for soluble prothrombin. Despite their very different affinities for soluble prothrombin, both monoclonal antibodies reacted similarly with prothrombin bound to phospholipid or apoptotic cells. Furthermore, both antibodies enhanced the binding of prothrombin to apoptotic cells. We propose that the recognition of apoptotic cells by these prothrombin-dependent monoclonal antibodies provides a paradigm for other anti-phospholipid autoantibodies. 29I4-24 is prototypical of phospholipid-dependent anti-phospholipid antibodies...

‣ Apoptotic Cells, at All Stages of the Death Process, Trigger Characteristic Signaling Events That Are Divergent from and Dominant over Those Triggered by Necrotic Cells: IMPLICATIONS FOR THE DELAYED CLEARANCE MODEL OF AUTOIMMUNITY*,S

Patel, Vimal A.; Longacre, Angelika; Hsiao, Kevin; Fan, Hanli; Meng, Fanyong; Mitchell, Justin E.; Rauch, Joyce; Ucker, David S.; Levine, Jerrold S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Current models of autoimmunity suggest that delayed clearance of apoptotic cells leads to the presentation of apoptotic antigens in the context of inflammatory signals, with resultant autoimmunity. These models implicitly assume that, in contrast to early apoptotic cells (that retain membrane integrity), late apoptotic cells (with compromised membranes) act like necrotic cells (which also lack intact membranes), possibly because of the release of proinflammatory intracellular contents. We showed previously that early apoptotic and necrotic cells induce distinct mitogen-activated protein kinase modules in macrophages with which they interact. Exposure to apoptotic cells led to nearly complete inhibition of both basal and macrophage colony-stimulating factor-induced ERK1/2 by macrophages. In contrast, necrotic cells induced ERK1/2. We show here that apoptotic cells also strongly induced both c-Jun N-terminal kinase and p38, whereas necrotic cells had no detectable effect on c-Jun N-terminal kinase and p38. We also compared the signaling events induced in macrophages by exposure to early apoptotic cells, late apoptotic cells, and necrotic cells. The signaling events induced by late apoptotic cells were identical to and just as potent as those induced by early apoptotic cells. Thus...

‣ Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein

Park, Daeho; Han, Claudia; Elliott, Michael R.; Kinchen, Jason M.; Trampont, Paul C.; Das, Soumita; Collins, Sheila; Lysiak, Jeffrey J.; Hoehn, Kyle L.; Ravichandran, Kodi S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 21/08/2011 Português
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Rapid and efficient removal of apoptotic cells by phagocytes plays a key role during development, tissue homeostasis, and in controlling immune responses1–5. An important feature of efficient clearance is the capacity of a single phagocyte to ingest multiple apoptotic cells successively, and to process the increased load of corpse-derived cellular material6–9. However, factors that influence sustained phagocytic capacity or how they in turn influence continued clearance by phagocytes are not known. Here we identify that the ability of a phagocyte to control its mitochondrial membrane potential is a critical factor in the capacity of a phagocyte to engulf apoptotic cells. Changing the phagocyte mitochondrial membrane potential (genetically or pharmacologically) significantly affected phagocytosis, with lower potential enhancing engulfment and higher membrane potential inhibiting uptake. We then identified that Ucp2, a mitochondrial membrane protein that acts to lower the mitochondrial membrane potential10–12, is upregulated in phagocytes engulfing apoptotic cells (but not synthetic targets, bacteria, or yeast). Loss of Ucp2 limited the capacity of phagocytes to continually ingest apoptotic cells, while overexpression of Ucp2 increased the capacity for engulfment and the ability to engulf multiple apoptotic cells. Mutational and pharmacological inhibition of Ucp2 uncoupling activity reversed the positive effect of Ucp2 on engulfment capacity...

‣ Innate recognition of apoptotic cells: novel apoptotic cell-associated molecular patterns revealed by crossreactivity of anti-LPS antibodies

Tennant, I; Pound, J D; Marr, L A; Willems, J J L P; Petrova, S; Ford, C A; Paterson, M; Devitt, A; Gregory, C D
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Cells dying by apoptosis are normally cleared by phagocytes through mechanisms that can suppress inflammation and immunity. Molecules of the innate immune system, the pattern recognition receptors (PRRs), are able to interact not only with conserved structures on microbes (pathogen-associated molecular patterns, PAMPs) but also with ligands displayed by apoptotic cells. We reasoned that PRRs might therefore interact with structures on apoptotic cells – apoptotic cell-associated molecular patterns (ACAMPs) – that are analogous to PAMPs. Here we show that certain monoclonal antibodies raised against the prototypic PAMP, lipopolysaccharide (LPS), can crossreact with apoptotic cells. We demonstrate that one such antibody interacts with a constitutively expressed intracellular protein, laminin-binding protein, which translocates to the cell surface during apoptosis and can interact with cells expressing the prototypic PRR, mCD14 as well as with CD14-negative cells. Anti-LPS cross reactive epitopes on apoptotic cells colocalised with annexin V- and C1q-binding sites on vesicular regions of apoptotic cell surfaces and were released associated with apoptotic cell-derived microvesicles (MVs). These results confirm that apoptotic cells and microbes can interact with the immune system through common elements and suggest that anti-PAMP antibodies could be used strategically to characterise novel ACAMPs associated not only with apoptotic cells but also with derived MVs.

‣ Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway

Pérez-Garijo, Ainhoa; Fuchs, Yaron; Steller, Hermann
Fonte: eLife Sciences Publications, Ltd Publicador: eLife Sciences Publications, Ltd
Tipo: Artigo de Revista Científica
Publicado em 24/09/2013 Português
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Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. We identified Eiger, the Drosophila tumor necrosis factor (TNF) homolog, as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. We also show that during coordinated cell death of hair follicle cells in mice, TNF-α is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions.

‣ Tim4- and MerTK-Mediated Engulfment of Apoptotic Cells by Mouse Resident Peritoneal Macrophages

Nishi, Chihiro; Toda, Satoshi; Segawa, Katsumori; Nagata, Shigekazu
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /04/2014 Português
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Apoptotic cells are swiftly engulfed by macrophages to prevent the release of noxious materials from dying cells. Apoptotic cells expose phosphatidylserine (PtdSer) on their surface, and macrophages engulf them by recognizing PtdSer using specific receptors and opsonins. Here, we found that mouse resident peritoneal macrophages expressing Tim4 and MerTK are highly efficient at engulfing apoptotic cells. Neutralizing antibodies against either Tim4 or MerTK inhibited the macrophage engulfment of apoptotic cells. Tim4-null macrophages exhibited reduced binding and engulfment of apoptotic cells, whereas MerTK-null macrophages retained the ability to bind apoptotic cells but failed to engulf them. The incubation of wild-type peritoneal macrophages with apoptotic cells induced the rapid tyrosine phosphorylation of MerTK, which was not observed with Tim4-null macrophages. When mouse Ba/F3 cells were transformed with Tim4, apoptotic cells bound to the transformants but were not engulfed. Transformation of Ba/F3 cells with MerTK had no effect on the binding or engulfment of apoptotic cells; however, Tim4/MerTK transformants exhibited strong engulfment activity. Taken together, these results indicate that the engulfment of apoptotic cells by resident peritoneal macrophages proceeds in two steps: binding to Tim4...

‣ Fetuin/α2-HS glycoprotein enhances phagocytosis of apoptotic cells and macropinocytosis by human macrophages.; Fetuin/alpha2-HS glycoprotein enhances phagocytosis of apoptotic cells and macropinocytosis by human macrophages.

Jersmann, H.; Dransfield, I.; Hart, S.
Fonte: Portland Press Publicador: Portland Press
Tipo: Artigo de Revista Científica
Publicado em //2003 Português
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Inflammatory diseases are associated with reduced serum concentrations of α2-HS glycoprotein (the human homologue of bovine fetuin), but the role of fetuin in inflammation is poorly understood. We hypothesized that fetuin may influence the resolution of inflammation by modulating the phagocytosis of apoptotic cells by macrophages. Using an in vitro flow cytometry-based phagocytosis assay, we investigated the role of fetuin in apoptotic cell clearance. Bovine fetuin and human Inflammatory diseases are associated with reduced serum concentrations of a2-HS glycoprotein (the human homologue of bovine fetuin), but the role of fetuin in inflammation is poorly understood. We hypothesized that fetuin may influence the resolution of inflammation by modulating the phagocytosis of apoptotic cells by macrophages. Using an in vitro flow cytometry-based phagocytosis assay, we investigated the role of fetuin in apoptotic cell clearance. Bovine fetuin and human α2-HS glycoprotein significantly augmented the phagocytosis of apoptotic cells by human peripheral blood monocyte-derived macrophages, whereas the control proteins BSA, sialylated BSA and asialofetuin were ineffective. The enhancement of phagocytosis was concentration-dependent, and required the presence of intact fetuin at the time of interaction between macrophages and apoptotic cells. Fetuin also substantially increased the uptake of labelled dextran 70000 by macrophages...

‣ Exposure and binding of selected immunodominant La/SSB epitopes on human apoptotic cells

Neufing, P.; Clancy, R.; Jackson, M.; Tran, H.; Buyon, J.; Gordon, T.
Fonte: Wiley-Liss Publicador: Wiley-Liss
Tipo: Artigo de Revista Científica
Publicado em //2005 Português
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573.7583%
OBJECTIVE: Opsonization of apoptotic cells by autoantibodies bound to surface membrane-translocated La/SSB antigens may initiate tissue damage in the setting of congenital heart block. By injecting pregnant mice with human anti-La antibodies, we previously demonstrated the formation of IgG-apoptotic cell complexes in the developing mouse fetus; however, the binding of anti-La antibodies to human-specific epitopes could not be addressed. Accordingly, the objective of the current study was to delineate the epitope specificity of human La antibodies that are exposed on the surface of apoptotic cells. METHODS: We used fluorescence microscopy and flow cytometry to assess the binding of human anti-La antibodies affinity purified against immunodominant epitopes of La to human cells undergoing spontaneous apoptosis, in a murine xenograft model in vivo and in cultured human fetal cardiocytes rendered apoptotic in vitro, respectively. RESULTS: Anti-La antibodies bound to immunodominant epitopes of La within the NH(2)-terminus and the RNA recognition motif (RRM) region of apoptotic human cells, in both xenografts and fetal cardiocytes. In contrast, human antibodies affinity purified against the COOH-terminal La epitope did not bind apoptotic cells in either model. This defines the topology of redistributed La during apoptosis...

‣ Efferocytosis Promotes Suppressive Effects on Dendritic Cells through Prostaglandin E2 Production in the Context of Autoimmunity

Pujol Autonell, Irma; Ampudia, Rosa-Maria; Planas, Raquel; Marin-Gallen, Silvia; Carrascal, Jorge; Sanchez, Alex; Marin, Ana; Puig Domingo, Manuel; Pujol Borrell, Ricardo; Verdaguer, Joan; Vives Pi, Marta
Fonte: Universidade Autônoma de Barcelona Publicador: Universidade Autônoma de Barcelona
Tipo: Artigo de Revista Científica Formato: application/pdf
Publicado em //2013 Português
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Introduction: Efferocytosis is a crucial process by which apoptotic cells are cleared by phagocytes, maintaining immune tolerance to self in the absence of inflammation. Peripheral tolerance, lost in autoimmune processes, may be restored by the administration of autologous dendritic cells loaded with islet apoptotic cells in experimental type 1 diabetes. Objective: to evaluate tolerogenic properties in dendritic cells induced by the clearance of apoptotic islet cells, thus explaining the re-establishment of tolerance in a context of autoimmunity. Methods: Bone marrow derived dendritic cells from non-obese diabetic mice, a model of autoimmune diabetes, were generated and pulsed with islet apoptotic cells. The ability of these cells to induce autologous T cell proliferation and to suppress mature dendritic cell function was assessed, together with cytokine production. Microarray experiments were performed using dendritic cells to identify differentially expressed genes after efferocytosis.Results: Molecular and functional changes in dendritic cells after the capture of apoptotic cells were observed. 1) Impaired ability of dendritic cells to stimulate autologous T cell proliferation after the capture of apoptotic cells even after proinflammatory stimuli...