Cell-Surface Calreticulin Initiates Clearance of Viable or Apoptotic Cells through trans-Activation of LRP on the Phagocyte

Gardai, Shyra J.; McPhillips, Kathleen A.; Frasch, S. Courtney; Janssen, William J.; Starefeldt, Anna; Murphy-Ullrich, Joanne E.; Bratton, Donna L.; Oldenborg, Per‐Arne; Michalak, Marek; Henson, Peter M.

doi:10.1016/j.cell.2005.08.032

Cited by 1,262 publications

(1,333 citation statements)

References 42 publications

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“…Recently, it has been suggested that calreticulin may function as a second general recognition ligand, via binding and activating LRP or CD91 on engulfing cells. 14 Arur et al 37 have suggested that annexin I may function in the facilitation of or enhancement of the recognition of PS by the receptor. Whether calreticulin or annexin I is related to stabilin-2-mediated phagocytosis is currently unclear, and will require further study.…”

Section: Discussionmentioning

confidence: 99%

“…9 In addition, several scavenger receptors have been theorized to mediate the binding and uptake of aged/apoptotic cells, including LOX-1, 10 CD36, 11 Drosophila Croquemort, 12 and low-density lipoprotein (LDL)-receptor-related protein (LRP1, also referred to as CD91). 13,14 These receptors may function in parallel or redundant phagocytic systems, as the blocking of any receptor impairs apoptotic cell engulfment only partially. 15 Although these receptors have been implicated in the engulfment of aged/apoptotic cells, no evidence has yet been presented to show that any of these receptors can directly recognize PS.…”

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confidence: 99%

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Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

et al. 2007

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Rapid phagocytic clearance of apoptotic cells is crucial for the prevention of both inflammation and autoimmune responses. Phosphatidylserine (PS) at the external surface of the plasma membrane has been proposed to function as a general 'eat me' signal for apoptotic cells. Although several soluble bridging molecules have been suggested for the recognition of PS, the PS-specific membrane receptor that binds directly to the exposed PS and provides a tickling signal has yet to be definitively identified. In this study, we provide evidence that stabilin-2 is a novel PS receptor, which performs a key function in the rapid clearance of cell corpses. It recognizes PS on aged red blood cells and apoptotic cells, and mediates their engulfment. The downregulation of stabilin-2 expression in macrophages significantly inhibits phagocytosis, and anti-stabilin-2 monoclonal antibody provokes the release of the anti-inflammatory cytokine, transforming growth factor-b. Furthermore, the results of timelapse video analyses indicate that stabilin-2 performs a crucial function in the rapid clearance of aged and apoptotic cells. These data indicate that stabilin-2 is the first of the membrane PS receptors to provide tethering and tickling signals, and may also be involved in the resolution of inflammation and the prevention of autoimmunity.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

et al. 2007

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“…31,32 Recently, calreticulin appearing on the surface of apoptotic cells was found to initiate their clearance acting together with PS for achieving optimal phagocytic clearance of cells. 33 Changing carbohydrate composition of glycoproteins 34 and exposure of DNA on dying cells 35 have been proposed as alternative mechanisms to PS for recognition of dead cells. Further studies are required to determine whether these alternative 'eat me' signals or others are exposed on the surface of cells dying through autophagy.…”

Section: Discussionmentioning

confidence: 99%

Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes

et al. 2007

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MCF-7 cells undergo autophagic death upon tamoxifen treatment. Plated on non-adhesive substratum these cells died by anoikis while inducing autophagy as revealed by monodansylcadaverine staining, elevated light-chain-3 expression and electron microscopy. Both de novo and anoikis-derived autophagic dying cells were engulfed by human macrophages and MCF-7 cells. Inhibition of autophagy by 3-methyladenine abolished engulfment of cells dying through de novo autophagy, but not those dying through anoikis. Blocking exposure of phosphatidylserine (PS) on both dying cell types inhibited phagocytosis by MCF-7 but not by macrophages. Gene expression profiling showed that though both types of phagocytes expressed full repertoire of the PS recognition and signaling pathway, macrophages could evolve during engulfment of de novo autophagic cells the potential of calreticulin-mediated processes as well. Our data suggest that cells dying through autophagy and those committing anoikis with autophagy may engage in overlapping but distinct sets of clearance mechanisms in professional and non-professional phagocytes.

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“…8 Other less-characterized recognition signals as well as the respective receptors they engage on phagocytes are depicted in Figure 2. [9][10][11] Factors such as the cell type undergoing death, the pathological or physiological stimulus, or the duration of this fatal process can affect the landscape of eat-me signals exposed.…”

Section: Steps Involved In Clearancementioning

confidence: 99%

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

2016

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The turnover and clearance of cells is an essential process that is part of many physiological and pathological processes. Improper or deficient clearance of apoptotic cells can lead to excessive inflammation and autoimmune disease. The steps involved in cell clearance include: migration of the phagocyte toward the proximity of the dying cells, specific recognition and internalization of the dying cell, and degradation of the corpse. The ability of phagocytes to recognize and react to dying cells to perform efficient and immunologically silent engulfment has been well-characterized in vitro and in vivo. However, how apoptotic cells themselves initiate the corpse removal and also influence the cells within the neighboring environment during clearance was less understood. Recent exciting observations suggest that apoptotic cells can attract phagocytes through the regulated release of 'find-me' signals. More recent studies also suggest that these find-me signals can have additional roles outside of phagocyte attraction to help orchestrate engulfment. This review will discuss our current understanding of the different find-me signals released by apoptotic cells, how they may be relevant in vivo, and their additional roles in facilitating engulfment.

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Cell-Surface Calreticulin Initiates Clearance of Viable or Apoptotic Cells through trans-Activation of LRP on the Phagocyte

Cited by 1,262 publications

References 42 publications

Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

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