scholarly journals Impaired Clearance of Apoptotic Cells Promotes Synergy between Atherogenesis and Autoimmune Disease

2004 ◽  
Vol 199 (8) ◽  
pp. 1121-1131 ◽  
Author(s):  
Tamar Aprahamian ◽  
Ian Rifkin ◽  
Ramon Bonegio ◽  
Bénédicte Hugel ◽  
Jean-Marie Freyssinet ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Apoptotic Cell ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
High Cholesterol Diet ◽  
Apoptotic Cells ◽  
Apoptotic Cell Clearance ◽  
Reduced Frequency ◽  
Cell Clearance

To clarify the link between autoimmune disease and hypercholesterolemia, we created the gld.apoE−/− mouse as a model of accelerated atherosclerosis. Atherosclerotic lesion area was significantly increased in gld.apoE−/− mice compared with apoE−/− mice. gld.apoE−/− mice also displayed increases in lymphadenopathy, splenomegaly, and autoantibodies compared with gld mice, and these effects were exacerbated by high cholesterol diet. gld.apoE−/− mice exhibited higher levels of apoptotic cells, yet a reduced frequency of engulfed apoptotic nuclei within macrophages. Infusion of lysophosphatidylcholine, a component of oxidized low density lipoprotein, markedly decreased apoptotic cell clearance in gld mice, indicating that hypercholesterolemia promotes autoimmune disease in this background. These data suggest that defects in apoptotic cell clearance promote synergy between atherosclerotic and autoimmune diseases.

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.

Abstract 457: CD36, but not G2A, Modulates Efferocytosis, Inflammation and Fibrosis Following Bleomycin-induced Lung Injury

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Leland L Black ◽  
Brian W Parks ◽  
Kurt A Zimmerman ◽  
Allison E Metz ◽  
Chad Steele ◽  
...  
Keyword(s):  
Lung Injury ◽  
Apoptotic Cell ◽  
Atherosclerotic Lesion ◽  
M2 Macrophage ◽  
Apoptotic Cells ◽  
Alveolar Cells ◽  
Lesion Development ◽  
Apoptotic Cell Clearance ◽  
Arginase 1 ◽  
Cell Clearance

Oxidatively modified lipids and their by-products presented or released by cells undergoing apoptosis are thought to regulate phagocytic uptake of apoptotic cells by macrophages (efferocytosis) through CD36 scavenger and G2A chemotactic receptors. Although the ability of these receptors to mediate clearance of apoptotic cells in the context of atherosclerosis may have significant impact on lesion development and progression/stability, an overabundance of the lipid ligands for these receptors (CD36: oxidized phospholipids, G2A: lysophosphatidylcholine) as a result of oxidative processes associated with atherogenesis could conceivably impair these clearance mechanisms. Because the indolent nature of atherosclerotic lesion development precludes an accurate assessment of the spatial and kinetic features of lesional efferocytosis, we employed a bleomycin-induced model of lung injury to assess the requirement for G2A and CD36 in efferocytosis. This is a model which, similarly to atherogenesis, is associated with oxidative stress, but in which local apoptosis can be induced and efferocytosis subsequently measured over time. As there is substantial in vivo evidence that ApoE has a role in efferocytosis, we included ApoE knock-out mice as controls. Loss of CD36 (similarly to ApoE deficiency) delayed the clearance of apoptotic alveolar cells, potentiated inflammation (increase in lung neutrophils, lung KC [CXCL1] levels, and lung macrophages) and reduced lung fibrosis following bleomycin-induced lung injury. Reduced fibrosis in CD36-/- mice was associated with lower levels of pro-fibrotic TH2 cytokines (IL-9, IL-13, IL-4), decreased expression of the M2 macrophage marker Arginase-1 and reduced interstitial myofibroblasts. Despite the widely held notion that G2A mediates an LPC dependent “find me” signal in macrophages facilitating apoptotic cell clearance, G2A deficiency had no significant effect on the clearance of apoptotic cells in the bleomycin-induced lung injury model. Our results show that CD36 and ApoE (but not G2A) are important for apoptotic cell clearance following lung injury and subsequently modulate inflammatory and fibrotic processes that could impact not only inflammatory lung disease but also atherosclerosis.

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 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 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 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 Opsonization of Early Apoptotic Cells by IgG from Lupus Nephritis Amplifies Activation of Early Complement Components and Promotes Inflammatory Phagocytosis

2020 ◽  
Author(s):  
Chenghua Wang ◽  
Bing Zhao ◽  
Xiang Liu ◽  
Xiaowei Yang
Keyword(s):  
Lupus Nephritis ◽  
Proinflammatory Cytokines ◽  
Complement Activation ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Complement Components ◽  
Early Apoptotic Cell ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Terminal Complement

Abstract Background SSA/Ro 60 has been reported to be exposed on the surface of early apoptotic cells and recognized by autoantibodies from lupus. The aim of this study was to explore the subsequent effects of the binding of IgG from anti-SSA positive LN patients on the fate of early apoptotic cells. Results IgG which have been confirmed with extensive binding to early apoptotic cells were purified from three anti-SSA positive LN patients. Opsonization of early apoptotic cells by IgG from LN augmented C3c deposition without influence on the assembly of the terminal complement components or cell lysis. IgG from LN enhanced opsonization and phagocytosis of early apoptotic cells by macrophages directly or dependent on complement activation, with massive TNF-a and IL-1β secretions. Conclusions IgG from anti-SSA positive LN facilitates early apoptotic cell clearance by macrophages and triggers proinflammatory cytokines release, possibly exacerbating underlying pathogenic mechanisms in lupus nephritis.

scholarly journals Protective Effects of Chinese Traditional Medicine Longhu Rendan against Atherosclerosis via Negative Regulation of LOX-1

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Sishan Yan ◽  
Teng Wu ◽  
Ning Li ◽  
Lingyi Zhang ◽  
Jun Song ◽  
...  
Keyword(s):  
Gene Knockout ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Serum Levels ◽  
Experimental Atherosclerosis ◽  
High Cholesterol Diet ◽  
Low Density ◽  
Protective Effects ◽  
Atherosclerosis Treatment

Longhu Rendan (LHRD), a Chinese traditional compound medicine, has a remarkable treatment effect on motion sickness for about half a century. However, the role of LHRD in atherosclerosis treatment is still unclear. In this study, LHRD treatment significantly diminished total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels in apolipoprotein E gene-knockout (ApoE-/-) mice fed with high fat and high cholesterol diet (western diet). Besides, LHRD treatment significantly reduced atherosclerotic lesion and plaques formation in both aortic roots and aortic trees. Furthermore, immunofluorescence staining in aortic roots demonstrated that LHRD treatment inhibited lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) expression in atherosclerotic plaques. These results indicated that LHRD ameliorated atherosclerosis via reducing serum levels of TC, TG, and LDL-C as well as LOX-1 expression, subsequently attenuating atherosclerotic lesion and lipid deposition. In conclusion, LHRD could significantly attenuate experimental atherosclerosis and might be a novel potential drug for the prevention and treatment of atherosclerosis.

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 Anti-Atherogenic Activity of Ethanolic Fraction ofTerminalia arjunaBark on Hypercholesterolemic Rabbits

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Saravanan Subramaniam ◽  
Ramachandran Subramaniam ◽  
Suja Rajapandian ◽  
Subasini Uthrapathi ◽  
Victor Rajamanickam Gnanamanickam ◽  
...  
Keyword(s):  
Body Weight ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Diet Group ◽  
Atherogenic Index ◽  
Terminalia Arjuna ◽  
High Cholesterol Diet ◽  
Low Density ◽  
Standard Drug

Atherosclerosis which results from gradual deposition of lipids in medium and large arteries is a leading cause of mortality worldwide.Terminalia arjunais a herb of Combretaceae family which contains hypolipidemic compounds and flavonoids with high antioxidative properties. This study was conducted to determine the effect of ethanolic fraction ofT. arjunaon blood lipids and atherosclerosis in rabbits fed with high fat diet (HFD). Twenty New Zealand rabbits of either sex were randomly divided into five groups: the first two were normal diet group and HFD (21% fat) group and the remaining three groups received high cholesterol diet supplemented with standard drug (Atorvastatin 10 mg kg−1body weight),T. arjunaethanolic fraction (100 and 200 mg kg−1body weight), respectively. The concentration of total cholesterol (TC), low density lipoprotein (LDL) cholesterol, triglycerides (TGs), very low density lipoprotein (VLDL) cholesterol and high density lipoprotein (HDL) cholesterol was determined in rabbits at the start of the experiment, at the 14th, 30th days and at the end of the study. Anti-atherogenic index was calculated from the lipid profile of the rabbits before sacrifice. At the end of the experimental period, the aorta was removed for assessment of atherosclerotic plaques. Results show thatT. arjunasignificantly decreases TC, LDL and TG levels and increases HDL and lessens atherosclerotic lesion in aorta (P< .05). HenceT. arjunaextract can effectively prevent the progress of atherosclerosis. This is likely due to the effect ofT. arjunaon serum lipoproteins and its antioxidant and anti-inflammatory properties.

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