scholarly journals Oxidized phosphatidylserine–CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells

2006 ◽  
Vol 203 (12) ◽  
pp. 2613-2625 ◽  
Author(s):  
Michael E. Greenberg ◽  
Mingjiang Sun ◽  
Renliang Zhang ◽  
Maria Febbraio ◽  
Roy Silverstein ◽  
...  
Keyword(s):  
Molecular Species ◽  
Essential Role ◽  
Apoptotic Cell ◽  
Scavenger Receptor ◽  
Apoptotic Cells ◽  
Class B ◽  
Oxidized Phosphatidylcholine ◽  
Cell Engulfment

The phagocytosis of apoptotic cells within an organism is a critical terminal physiological process in programmed cell death. Evidence suggests that apoptotic cell engulfment and removal by macrophages is facilitated by phosphatidylserine (PS) displayed at the exofacial surface of the plasma membrane; however, neither the macrophage receptors responsible for PS recognition, nor characterization of the PS molecular species potentially involved, have been clearly defined. We show that the class B scavenger receptor CD36 plays an essential role in macrophage clearance of apoptotic cells in vivo. Further, macrophage recognition of apoptotic cells via CD36 is shown to occur via interactions with membrane-associated oxidized PS (oxPS) and, to a lesser extent, oxidized phosphatidylcholine, but not nonoxidized PS molecular species. Mass spectrometry analyses of oxPS species identify structures of candidate ligands for CD36 in apoptotic membranes that may facilitate macrophage recognition. Collectively, these results identify oxPS–CD36 interactions on macrophages as potential participants in a broad range of physiologic processes where macrophage-mediated engulfment of apoptotic cells is involved.

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 Two Alternative Mechanisms That Regulate the Presentation of Apoptotic Cell Engulfment Signal in Caenorhabditis elegans

2007 ◽  
Vol 18 (8) ◽  
pp. 3180-3192 ◽  
Author(s):  
Victor Venegas ◽  
Zheng Zhou
Keyword(s):  
Caenorhabditis Elegans ◽  
Abc Transporter ◽  
Germ Cells ◽  
Mammalian Cells ◽  
Developmental Stages ◽  
Apoptotic Cell ◽  
Somatic Cells ◽  
Apoptotic Cells ◽  
Phospholipid Scramblase ◽  
Cell Engulfment

Phosphatidylserine exposed on the surface of apoptotic mammalian cells is considered an “eat-me” signal that attracts phagocytes. The generality of using phosphatidylserine as a clearance signal for apoptotic cells in animals and the regulation of this event remain uncertain. Using ectopically expressed mouse MFG-E8, a secreted phosphatidylserine-binding protein, we detected specific exposure of phosphatidylserine on the surface of apoptotic cells in Caenorhabditis elegans. Masking the surface phosphatidylserine inhibits apoptotic cell engulfment. CED-7, an ATP-binding cassette (ABC) transporter, is necessary for the efficient exposure of phosphatidylserine on apoptotic somatic cells, and for the recognition of these cells by phagocytic receptor CED-1. Alternatively, phosphatidylserine exposure on apoptotic germ cells is not CED-7 dependent, but instead requires phospholipid scramblase PLSC-1, a homologue of mammalian phospholipid scramblases. Moreover, deleting plsc-1 results in the accumulation of apoptotic germ cells but not apoptotic somatic cells. These observations suggest that phosphatidylserine might be recognized by CED-1 and act as a conserved eat-me signal from nematodes to mammals. Furthermore, the two different biochemical activities used in somatic cells (ABC transporter) and germ cells (phospholipid scramblase) suggest an increased complexity in the regulation of phosphatidylserine presentation in response to apoptotic signals in different tissues and during different developmental stages.

Characterization of scavenger receptor class B, type I in Atlantic salmon (Salmo salar L.)

Lipids ◽  
2006 ◽  
Vol 41 (11) ◽  
pp. 1017-1027 ◽  
Author(s):  
E. J. Kleveland ◽  
B. L. Syvertsen ◽  
B. Ruyter ◽  
A. Vegusdal ◽  
S. M. Jørgensen ◽  
...  
Keyword(s):  
Atlantic Salmon ◽  
Salmo Salar ◽  
Scavenger Receptor ◽  
Type I ◽  
Atlantic Salmon Salmo Salar ◽  
Scavenger Receptor Class ◽  
Class B

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 Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE2and HGF Expression via a Positive Feedback Loop

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Ji Yeon Byun ◽  
Young-So Youn ◽  
Ye-Ji Lee ◽  
Youn-Hee Choi ◽  
So-Yeon Woo ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Tissue Repair ◽  
Feedback Loop ◽  
Apoptotic Cell ◽  
Raw 264.7 Cells ◽  
Apoptotic Cells ◽  
Positive Feedback Loop ◽  
Cox 2

Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cellsin vitroandin vivoorchestrate the interaction between COX-2/PGE2and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2production. Both NS-398 and COX-2-siRNA, as well as the PGE2receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2induction. Thein vivorelevance of the interaction between the COX-2/PGE2and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages followingin vivoexposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

scholarly journals A Human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo

Hepatology ◽  
2011 ◽  
Vol 55 (2) ◽  
pp. 364-372 ◽  
Author(s):  
Philip Meuleman ◽  
Maria Teresa Catanese ◽  
Lieven Verhoye ◽  
Isabelle Desombere ◽  
Ali Farhoudi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Human Monoclonal Antibody ◽  
Scavenger Receptor ◽  
Type I ◽  
Hepatitis C Virus Infection ◽  
Viral Spread ◽  
Scavenger Receptor Class ◽  
Class B

scholarly journals p21-activated Kinase-1 (PAK1) Inhibition of the Human Scavenger Receptor Class B, Type I Promoter in Macrophages Is Independent of PAK1 Kinase Activity, but Requires the GTPase-binding Domain

2001 ◽  
Vol 276 (50) ◽  
pp. 46807-46814 ◽  
Author(s):  
Thomas G. Hullinger ◽  
Robert L. Panek ◽  
Xiangyang Xu ◽  
Sotirios K. Karathanasis
Keyword(s):  
High Density Lipoprotein ◽  
Promoter Activity ◽  
Kinase Activity ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Type I ◽  
Down Regulation ◽  
Scavenger Receptor Class ◽  
Class B

Scavenger receptor class B, type I (SR-BI), is a high density lipoprotein receptor that mediates the flux of cholesterol between high density lipoprotein and cells. Recent evidence suggests that SR-BI plays a role in atherosclerosis and that inflammatory mediators down-regulate SR-BI in the macrophage. The purpose of this study was to evaluate the ability of lipopolysaccharide (LPS) to down-regulate the activity of the human SR-BI promoter in the macrophage and to delineate the mechanisms involved. Experiments with cultured cells andin vivoderived macrophages showed that LPS has a powerful suppressive effect on SR-BI expression bothin vitroandin vivo. Transient transfection studies demonstrated that LPS represses SR-BI promoter activity in the macrophage cell line RAW 264.7. Cotransfection with either a constitutively active p21-activated protein kinase-1 (PAK1) construct (T423E) or a kinase-deficient PAK1 construct (K299R) resulted in repression of the SR-BI promoter, similar to LPS. These results demonstrate that PAK1-mediated down-regulation of the SR-BI promoter is independent of PAK1 kinase activity and suggest that PAK1 mediates the LPS-induced decrease in promoter activity. Cotransfection with constitutively active Cdc42 or Rac expression constructs also resulted in down-regulation of the promoter; whereas the dominant-negative Cdc42 and Rac constructs elevated basal promoter activity and blunted the LPS response. Cotransfection of PAK1 constructs containing mutations in both the kinase domain and the Cdc42/Rac-binding domain attenuated the PAK1-mediated down-regulation of the promoter, suggesting that Rac and Cdc42 are required for PAK1-mediated decreases in SR-BI promoter activity. 5′-Deletion analysis and gel shift data suggest that LPS inhibits binding of a novel transcription factor to a myeloid zing finger protein-1-like element (−476 to −456) in the human SR-BI promoter. These results demonstrate that the PAK1 pathway down-regulates the SR-BI promoter and suggest that activation of this pathway may play an important role in cholesterol trafficking in the vessel wall.

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