scholarly journals Clearance of apoptotic cells: implications in health and disease

2010 ◽  
Vol 189 (7) ◽  
pp. 1059-1070 ◽  
Author(s):  
Michael R. Elliott ◽  
Kodi S. Ravichandran
Keyword(s):  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Molecular Signaling ◽  
Molecular Alterations ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Evolutionarily Conserved ◽  
Health And Disease ◽  
Process Studies ◽  
Dying Cells

Recent advances in defining the molecular signaling pathways that regulate the phagocytosis of apoptotic cells have improved our understanding of this complex and evolutionarily conserved process. Studies in mice and humans suggest that the prompt removal of dying cells is crucial for immune tolerance and tissue homeostasis. Failed or defective clearance has emerged as an important contributing factor to a range of disease processes. This review addresses how specific molecular alterations of engulfment pathways are linked to pathogenic states. A better understanding of the apoptotic cell clearance process in healthy and diseased states could offer new therapeutic strategies.

scholarly journals Chemokines as phosphatidylserine-bound ‘find-me’ signals in apoptotic cell clearance

2020 ◽  
Author(s):  
Sergio M. Pontejo ◽  
Philip M. Murphy
Keyword(s):  
Extracellular Vesicles ◽  
Chemokine Receptors ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Anionic Phospholipid ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Cell Plasma ◽  
Signal Activity ◽  
Dying Cells

AbstractChemokines are positively charged cytokines that attract leukocytes by binding to anionic glycosaminoglycans (GAGs) on endothelial cells for efficient presentation to leukocyte G protein-coupled receptors (GPCRs). The atypical chemokine CXCL16 has been reported to also bind the anionic phospholipid phosphatidylserine (PS), but the biological relevance of this interaction remains poorly understood. Here we demonstrate that PS binding is in fact a widely shared property of chemokine superfamily members that, like GAG binding, induces chemokine oligomerization. PS is an essential phospholipid of the inner leaflet of the healthy cell plasma membrane but it is exposed in apoptotic cells to act as an ‘eat-me’ signal that promotes engulfment of dying cells by phagocytes. We found that chemokines can bind PS in pure form as well as in the context of liposomes and on the surface of apoptotic cells and extracellular vesicles released by apoptotic cells, which are known to act as ‘find-me’ signals that chemoattract phagocytes during apoptotic cell clearance. Importantly, we show that GAGs are severely depleted from the surface of apoptotic cells and that extracellular vesicles extracted from apoptotic mouse thymus bind endogenous thymic chemokines and activate cognate chemokine receptors. Together these results indicate that chemokines tethered to surface-exposed PS may be responsible for the chemotactic and find-me signal activity previously attributed to extracellular vesicles, and that PS may substitute for GAGs as the anionic scaffold that regulates chemokine oligomerization and presentation to GPCRs on the GAG-deficient membranes of apoptotic cells and extracellular vesicles. Here, we present a new mechanism by which extracellular vesicles, currently recognized as essential agents for intercellular communication in homeostasis and disease, can transport signaling cytokines.

scholarly journals Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums

2010 ◽  
Vol 207 (9) ◽  
pp. 1807-1817 ◽  
Author(s):  
Kodi S. Ravichandran
Keyword(s):  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
New Information ◽  
Multiple Receptors ◽  
Dying Cells

Everyday we turnover billions of cells. The quick, efficient, and immunologically silent disposal of the dying cells requires a coordinated orchestration of multiple steps, through which phagocytes selectively recognize and engulf apoptotic cells. Recent studies have suggested an important role for soluble mediators released by apoptotic cells that attract phagocytes (“find-me” signals). New information has also emerged on multiple receptors that can recognize phosphatidylserine, the key “eat-me” signal exposed on the surface of apoptotic cells. This perspective discusses recent exciting progress, gaps in our understanding, and the conflicting issues that arise from the newly acquired knowledge.

scholarly journals TNFα inhibits apoptotic cell clearance in the lung, exacerbating acute inflammation

2009 ◽  
Vol 297 (4) ◽  
pp. L586-L595 ◽  
Author(s):  
Valeria M. Borges ◽  
R. William Vandivier ◽  
Kathleen A. McPhillips ◽  
Jennifer A. Kench ◽  
Konosuke Morimoto ◽  
...  
Keyword(s):  
Lung Injury ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Neutrophil Accumulation ◽  
Cell Recruitment ◽  
Apoptotic Cell Clearance ◽  
Persistent Inflammation ◽  
Cell Clearance ◽  
Proinflammatory Responses ◽  
Dying Cells

Efficient removal of apoptotic cells is essential for resolution of inflammation. Failure to clear dying cells can exacerbate lung injury and lead to persistent inflammation and autoimmunity. Here we show that TNFα blocks apoptotic cell clearance by alveolar macrophages and leads to proinflammatory responses in the lung. Compared with mice treated with intratracheal TNFα or exogenous apoptotic cells, mice treated with the combination of TNFα plus apoptotic cells demonstrated reduced apoptotic cell clearance from the lungs and increased recruitment of inflammatory leukocytes to the air spaces. Treatment with intratracheal TNFα had no effect on the removal of exogenous apoptotic cells from the lungs of TNFα receptor-1 (p55) and -2 (p75) double mutant mice and no effect on leukocyte recruitment. Bronchoalveolar lavage from mice treated with TNFα plus apoptotic cells contained increased levels of proinflammatory cytokines IL-6, KC, and MCP-1, but exhibited no change in levels of anti-inflammatory cytokines IL-10 and TGF-β. Administration of TNFα plus apoptotic cells during LPS-induced lung injury augmented neutrophil accumulation and proinflammatory cytokine production. These findings suggest that the presence of TNFα in the lung can alter the response of phagocytes to apoptotic cells leading to inflammatory cell recruitment and proinflammatory mediator production.

scholarly journals Microglia in the developing retina couple phagocytosis with the progression of apoptosis via P2RY12 signaling

2020 ◽  
Author(s):  
Zachary I. Blume ◽  
Jared M. Lambert ◽  
Anna G. Lovel ◽  
Diana M. Mitchell
Keyword(s):  
Real Time ◽  
Apoptotic Cell ◽  
List Type ◽  
Apoptotic Cells ◽  
Real Time Imaging ◽  
Microglial Phagocytosis ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Dying Cells

AbstractBackgroundMicroglia colonize the developing vertebrate central nervous system coincident with detection of developmental apoptosis. Our understanding of apoptosis in intact tissue in relation to microglial clearance of dying cells is largely based on fixed samples, which is limiting given that microglia are highly motile and mobile phagocytes. Here, we used a system of microglial depletion and in vivo real-time imaging in zebrafish to directly address microglial phagocytosis of apoptotic cells during normal retinal development, the relative timing of phagocytosis in relation to apoptotic progression, and the contribution of P2RY12 signaling to this process.ResultsDepletion of microglia resulted in accumulation of numerous apoptotic cells in the retina. Real-time imaging revealed precise timing of microglial engulfment with the progression of apoptosis, and dynamic movement and displacement of engulfed apoptotic cells. Inhibition of P2RY12 signaling delayed microglial clearance of apoptotic cells.ConclusionsMicroglial engulfment of dying cells is coincident with apoptotic progression and requires P2RY12 signaling, indicating that microglial P2RY12 signaling is shared between development and injury response. Our work provides important in vivo insight into the dynamics of apoptotic cell clearance in the developing vertebrate retina and provides a basis to understand microglial phagocytic behavior in health and disease.Bullet PointsLevels and location of developmental apoptosis in the zebrafish retina are elusive due to rapid and efficient clearance by microgliaMicroglial clearance of apoptotic cells is timed with the progression of apoptosis of the engulfed cell so that many cells are cleared in relatively early apoptotic stagesP2RY12 signaling is involved in microglial sensing and clearance of cells undergoing normal developmental apoptosis, indicating shared signals in microglial responses to cell death in both healthy and injured tissueGrant SponsorsNIH NIGMS Grant No. P20 GM103408

Apoptosis in the lung: induction, clearance and detection

2008 ◽  
Vol 294 (4) ◽  
pp. L601-L611 ◽  
Author(s):  
P. M. Henson ◽  
R. M. Tuder
Keyword(s):  
Cell Death ◽  
Tissue Repair ◽  
Alternative Explanation ◽  
Apoptotic Cell ◽  
Lung Cells ◽  
Apoptotic Cells ◽  
Local Responses ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Dying Cells

Apoptosis and other forms of programmed cell death are important contributors to lung pathophysiology. In this brief review, we discuss some of the implications of finding apoptotic cells in the lung and methods for their detection. The balance between induction of apoptosis and the normally highly efficient clearance of such cells shows that these are highly dynamic processes and suggests that abnormalities of apoptotic cell clearance may be an alternative explanation for their detection. Because recognition of apoptotic cells by other lung cells has additional effects on inflammation, immunity, and tissue repair, local responses to the dying cells may also have important consequences in addition to the cell death itself.

scholarly journals Simu-dependent clearance of dying cells regulates macrophage function and inflammation resolution

2018 ◽  
Author(s):  
Hannah Grace Roddie ◽  
Emma Louise Armitage ◽  
Simon Andrew Johnston ◽  
Iwan Robert Evans
Keyword(s):  
Normal Development ◽  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Clearance Receptor ◽  
Inflammation Resolution ◽  
Dying Cells ◽  
Inflammatory Action

AbstractMacrophages encounter and clear apoptotic cells during normal development and homeostasis, including at numerous sites of pathology. Clearance of apoptotic cells has been intensively studied, but the effects of macrophage-apoptotic cell interactions on macrophage behaviour are poorly understood. Using Drosophila embryos, we have exploited the ease of manipulating cell death and apoptotic cell clearance in this model to identify that the loss of the apoptotic cell clearance receptor Simu leads to perturbation of macrophage migration and inflammatory responses via pathological levels of apoptotic cells. Removal of apoptosis ameliorates these phenotypes, while acute induction of apoptosis phenocopies these defects and reveals that phagocytosis of apoptotic cells is not necessary for their anti-inflammatory action. Furthermore, Simu is necessary for clearance of necrotic debris and rentention of macrophages at wounds. Thus, Simu is a general detector of damaged self and represents a novel molecular player in controlling resolution of inflammation.

scholarly journals Overexposure to apoptosis via disrupted glial specification perturbs Drosophila macrophage function and reveals roles of the CNS during injury

2020 ◽  
Author(s):  
Emma Louise Armitage ◽  
Hannah Grace Roddie ◽  
Iwan Robert Evans
Keyword(s):  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Calcium Waves ◽  
Apoptotic Cells ◽  
Phagocytic Cells ◽  
Macrophage Function ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Wound Responses

AbstractApoptotic cell clearance by phagocytes is a fundamental process during development, homeostasis and the resolution of inflammation. However, the demands placed on phagocytic cells such as macrophages by this process, and the limitations these interactions impose on subsequent cellular behaviours are not yet clear. Here we seek to understand how apoptotic cells affect macrophage function in the context of a genetically-tractable Drosophila model in which macrophages encounter excessive amounts of apoptotic cells. We show that loss of the glial transcription factor repo, and corresponding removal of the contribution these cells make to apoptotic cell clearance, causes macrophages in the developing embryo to be challenged with large numbers of apoptotic cells. As a consequence, macrophages become highly vacuolated with cleared apoptotic cells and their developmental dispersal and migration is perturbed. We also show that the requirement to deal with excess apoptosis caused by a loss of repo function leads to impaired inflammatory responses to injury. However, in contrast to migratory phenotypes, defects in wound responses cannot be rescued by preventing apoptosis from occurring within a repo mutant background. In investigating the underlying cause of these impaired inflammatory responses, we demonstrate that wound-induced calcium waves propagate into surrounding tissues, including neurons and glia of the ventral nerve cord, which exhibit striking calcium waves on wounding, revealing a previously unanticipated contribution of these cells during responses to injury. Taken together these results demonstrate important insights into macrophage biology and how repo mutants can be used to study macrophage-apoptotic cell interactions in the fly embryo.Furthermore, this work shows how these multipurpose cells can be ‘overtasked’ to the detriment of their other functions, alongside providing new insights into which cells govern macrophage responses to injury in vivo.

scholarly journals Persistence of apoptotic cells without autoimmune disease or inflammation in CD14−/− mice

2004 ◽  
Vol 167 (6) ◽  
pp. 1161-1170 ◽  
Author(s):  
Andrew Devitt ◽  
Kate G. Parker ◽  
Carol Anne Ogden ◽  
Ceri Oldreive ◽  
Michael F. Clay ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Autoantibody Production ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Surface Receptor ◽  
Anti Inflammatory

Interaction of macrophages with apoptotic cells involves multiple steps including recognition, tethering, phagocytosis, and anti-inflammatory macrophage responses. Defective apoptotic cell clearance is associated with pathogenesis of autoimmune disease. CD14 is a surface receptor that functions in vitro in the removal of apoptotic cells by human and murine macrophages, but its mechanism of action has not been defined. Here, we demonstrate that CD14 functions as a macrophage tethering receptor for apoptotic cells. Significantly, CD14−/− macrophages in vivo are defective in clearing apoptotic cells in multiple tissues, suggesting a broad role for CD14 in the clearance process. However, the resultant persistence of apoptotic cells does not lead to inflammation or increased autoantibody production, most likely because, as we show, CD14−/− macrophages retain the ability to generate anti-inflammatory signals in response to apoptotic cells. We conclude that CD14 plays a broad tethering role in apoptotic cell clearance in vivo and that apoptotic cells can persist in the absence of proinflammatory consequences.

scholarly journals C4d Deposition after Allogeneic Renal Transplantation in Rats Is Involved in Initial Apoptotic Cell Clearance

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3499
Author(s):  
Stefan Reuter ◽  
Dominik Kentrup ◽  
Alexander Grabner ◽  
Gabriele Köhler ◽  
Konrad Buscher ◽  
...  
Keyword(s):  
Complement Activation ◽  
Apoptotic Cell ◽  
Human Kidney ◽  
Positive Staining ◽  
Apoptotic Cells ◽  
Complement Factors ◽  
Antibody Mediated Rejection ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Renal Transplantations

In the context of transplantation, complement activation is associated with poor prognosis and outcome. While complement activation in antibody-mediated rejection is well-known, less is known about complement activation in acute T cell-mediated rejection (TCMR). There is increasing evidence that complement contributes to the clearance of apoptotic debris and tissue repair. In this regard, we have analysed published human kidney biopsy transcriptome data clearly showing upregulated expression of complement factors in TCMR. To clarify whether and how the complement system is activated early during acute TCMR, experimental syngeneic and allogeneic renal transplantations were performed. Using an allogeneic rat renal transplant model, we also observed upregulation of complement factors in TCMR in contrast to healthy kidneys and isograft controls. While staining for C4d was positive, staining with a C3d antibody showed no C3d deposition. FACS analysis of blood showed the absence of alloantibodies that could have explained the C4d deposition. Gene expression pathway analysis showed upregulation of pro-apoptotic factors in TCMR, and apoptotic endothelial cells were detected by ultrastructural analysis. Monocytes/macrophages were found to bind to and phagocytise these apoptotic cells. Therefore, we conclude that early C4d deposition in TCMR may be relevant to the clearance of apoptotic cells.

scholarly journals Conserved and Distinct Elements of Phagocytosis in Human and C. elegans

2021 ◽  
Vol 22 (16) ◽  
pp. 8934
Author(s):  
Szilvia Lukácsi ◽  
Zsolt Farkas ◽  
Éva Saskői ◽  
Zsuzsa Bajtay ◽  
Krisztina Takács-Vellai
Keyword(s):  
Apoptotic Cell ◽  
Host Cells ◽  
Cellular Damage ◽  
Phagocytic Cells ◽  
C Elegans ◽  
Apoptotic Cell Clearance ◽  
Vital Functions ◽  
Cell Clearance ◽  
Infected Cells ◽  
Dying Cells

Endocytosis provides the cellular nutrition and homeostasis of organisms, but pathogens often take advantage of this entry point to infect host cells. This is counteracted by phagocytosis that plays a key role in the protection against invading microbes both during the initial engulfment of pathogens and in the clearance of infected cells. Phagocytic cells balance two vital functions: preventing the accumulation of cell corpses to avoid pathological inflammation and autoimmunity, whilst maintaining host defence. In this review, we compare elements of phagocytosis in mammals and the nematode Caenorhabditis elegans. Initial recognition of infection requires different mechanisms. In mammals, pattern recognition receptors bind pathogens directly, whereas activation of the innate immune response in the nematode rather relies on the detection of cellular damage. In contrast, molecules involved in efferocytosis—the engulfment and elimination of dying cells and cell debris—are highly conserved between the two species. Therefore, C. elegans is a powerful model to research mechanisms of the phagocytic machinery. Finally, we show that both mammalian and worm studies help to understand how the two phagocytic functions are interconnected: emerging data suggest the activation of innate immunity as a consequence of defective apoptotic cell clearance.

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