Reduced expression of CD47 during murine red blood cell (RBC) senescence and its role in RBC clearance from the circulation

Khandelwal, Sanjay; Rooijen, Nico van; Saxena, Rajiv K.

doi:10.1111/j.1537-2995.2007.01348.x

Cited by 160 publications

(138 citation statements)

References 24 publications

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“…28,29 It was speculated that loss of CD47 on older RBCs might be one factor facilitating their removal from the circulation. However, our present findings indicate that the role of CD47 in this process might be dependent on how the senescent RBC is interacting with the analyzed by flow cytometry to confirm equal opsonization, using FITC anti-mouse IgG.…”

Section: Discussionmentioning

confidence: 99%

“…27 Aged RBCs in circulation were also shown to express reduced levels of CD47. 28,29 We therefore compared phagocytosis of IgG-opsonized WT, CD47 ϩ/Ϫ , or CD47 Ϫ/Ϫ Ox-RBCs. Both in the presence and absence of serum, phagocytosis of CD47 ϩ/Ϫ Ox-RBCs was significantly elevated compared with that of WT Ox-RBCs, but significantly reduced compared with CD47 Ϫ/Ϫ Ox-RBCs ( Figure 5).…”

Section: Cd47 On Ox-rbcs Can Still Inhibit Fc␥r-mediated Phagocytosismentioning

confidence: 99%

“…27 We have shown that the phagocytosis-inhibitory effect of CD47 does not come into play on apoptotic nucleated cells, where CD47 is clustered into patches on the apoptotic cell surface and segregated away from prophagocytic ligands such as PS or calreticulin. 25 Although older circulating RBCs were found to express reduced levels of CD47, 28,29 little is known about the function of CD47 during RBC senescence and in regulating macrophage phagocytosis of senescent RBCs. Therefore, the aim of the present study was to investigate the role of CD47 in regulating macrophage phagocytosis of experimentally senescent RBCs.…”

Section: Introductionmentioning

confidence: 99%

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CD47 on experimentally senescent murine RBCs inhibits phagocytosis following Fcγ receptor–mediated but not scavenger receptor–mediated recognition by macrophages

Olsson

Oldenborg

2008

Blood

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IntroductionRemoval of senescent red blood cells (RBCs) from the circulation is a selective process mediated mainly by macrophages in the liver and spleen. 1 Several molecular patterns, which may be involved as ligands in recognition by macrophages, appear on the surface of senescent RBCs. Macrophages can either directly recognize these ligands, or recognition can be dependent on binding of bridging plasma proteins that may interact with the RBC ligands. [2][3][4][5][6][7] As such, these RBC ligands may include alterations in protein carbohydrate moieties, 8 loss of plasma membrane phospholipid asymmetry, [9][10][11] and/or clustering of Band 3 with subsequent binding of complement or antibodies. 12-14 Phagocytosis by macrophages can for instance be induced following ligation of receptors such as Fc␥ receptors (Fc␥R), complement receptors, or scavenger receptors (SRs). [15][16][17] Fc␥R recognizes the Fc portion of immunoglobulin G (IgG) bound to a target cell, resulting in rapid phagocytosis of the IgG-opsonized target. SRs make up a large family of receptors with a broad ligand-binding ability, where most known ligands are polyanionic molecules such as proteins, polyribonucleotides, polysaccharides, and lipids. 16 "Altered" host molecules (eg, oxidized low-density lipoprotein [oxLDL]) can be recognized by most SRs, whereas other ligands interact more specifically with SRs. 16 Oxidative damage is likely to be one important cause of RBC senescence and exposure of senescence-associated ligands. 13,18 RBCs oxidized in vitro (Ox-RBCs) are efficiently phagocytosed by macrophages in the absence of further opsonization, a process shown to be inhibited by oxLDL or other SR ligands, such as fucoidan, dextran sulfate, or poly-I, both in vivo and in vitro. 4,7,19 Phagocytosis of Ox-RBCs has also been suggested to be serum dependent, 6 and involve recognition of phosphatidylserine (PS) on the RBC surface. 9,10 Macrophage phagocytosis of target host cells is regulated by the balance between signaling through prophagocytic receptors (eg, Fc␥R or complement receptors) and inhibitory receptors. Recognition of the cell surface glycoprotein CD47 by the inhibitory receptor signal regulatory protein alpha (SIRP␣) inhibits phagocytosis of unopsonized RBCs, as well as IgG or complementopsonized RBCs, both in vivo and in vitro. 20-23 CD47 is highly expressed on RBCs, but ubiquitously expressed by most cells in the body, and can also negatively regulate phagocytosis of platelets and leukocytes. [24][25][26] The amount of CD47 on the cell surface regulates macrophage phagocytosis, since IgG-opsonized RBCs from CD47 ϩ/Ϫ mice (expressing about 50% of normal levels of CD47) are taken up faster than wild-type (WT) RBCs, but slower than CD47 Ϫ/Ϫ RBCs. 27 We have shown that the phagocytosis-inhibitory effect of CD47 does not come into play on apoptotic nucleated cells, where CD47 is clustered into patches on the apoptotic cell surface and segregated away from prophagocytic ligands such as PS or calreticulin. 25 Although older circulating RBC...

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Section: Discussionmentioning

confidence: 99%

Section: Cd47 On Ox-rbcs Can Still Inhibit Fc␥r-mediated Phagocytosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CD47 on experimentally senescent murine RBCs inhibits phagocytosis following Fcγ receptor–mediated but not scavenger receptor–mediated recognition by macrophages

Olsson

Oldenborg

2008

Blood

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“…Surface modulations include external exposure of membrane phosphatidylserine (PS), decreased membrane fluidity, decreased levels of sialic acid and CD47 and binding of autologous immunoglobulins and opsonins. 3,[6][7][8][9][10][11][12][13] In addition, RBC are naturally damaged by oxidation during aging and a number of molecular modifications induced by oxidative stress such as PS externalization have been observed in sRBC. 3,14 Some of these modulations are recognized by macrophages as senescence signals but the relative contribution of these signals to EPC is not known.…”

Section: Introductionmentioning

confidence: 99%

Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro

Gottlieb¹,

Topaz²,

Cohen³

et al. 2012

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe lifespan of red blood cells is terminated when macrophages remove senescent red blood cells by erythrophagocytosis. This puts macrophages at the center of systemic iron recycling in addition to their functions in tissue remodeling and innate immunity. Thus far, erythrophagocytosis has been studied by evaluating phagocytosis of erythrocytes that were damaged to mimic senescence. These studies have demonstrated that acquisition of some specific individual senescence markers can trigger erythrophagocytosis by macrophages, but we hypothesized that the mechanism of erythrophagocytosis of such damaged erythrocytes might differ from erythrophagocytosis of physiologically aged erythrocytes. Design and MethodsTo test this hypothesis we generated an erythrocyte population highly enriched in senescent erythrocytes by a hypertransfusion procedure in mice. Various erythrocyte-aging signals were analyzed and erythrophagocytosis was evaluated in vivo and in vitro. ResultsThe large cohort of senescent erythrocytes from hypertransfused mice carried numerous aging signals identical to those of senescent erythrocytes from control mice. Phagocytosis of fluorescently-labeled erythrocytes from hypertransfused mice injected into untreated mice was much higher than phagocytosis of labeled erythrocytes from control mice. However, neither erythrocytes from hypertransfused mice, nor those from control mice were phagocytosed in vitro by primary macrophage cultures, even though these cultures were able to phagocytose oxidatively damaged erythrocytes. ConclusionsThe large senescent erythrocyte population found in hypertransfused mice mimics physiologically aged erythrocytes. For effective erythrophagocytosis of these senescent erythrocytes, macrophages depend on some features of the intact phagocytosing tissue for support. ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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“…The removal of abnormal or senescent RBCs, which is now regarded as a particular apoptotic phenomenon (18)(19)(20)(21) called erythroptosis (22), involves macrophagic phagocytosis either when the nonphagocytotic CD47 signal is decreased (23) or when phagocytosis-triggering signals (desialylation of glycoproteins, the signal for the capture of RBCs and phosphatydylserine externalization, the signal for their phagocytosis) are exposed (18). Many modifications of the properties of RBCs, including morphological changes, reduce RBC deformability, which in turn facilitates their sequestration within blood vessels of the spleen and phagocytosis by splenic macrophages (24).…”

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confidence: 99%

A cytometric study of the red blood cells in Gaucher disease reveals their abnormal shape that may be involved in increased erythrophagocytosis

Bratosin

Tissier²,

Lapillonne

et al. 2010

Cytometry

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Background: Gaucher disease is a sphingolipidosis caused by a deficiency of the enzyme glucocerebrosidase. Macrophages transform into pathogenic Gaucher cells following the phagocytosis of red blood cells (RBCs) and subsequent accumulation of glucosylceramide. Enhanced erythrophagocytosis is one feature of the disease indicating abnormal macrophage-RBC interactions. We hypothesized that the erythrophagocytosis observed in Gaucher disease may be at least partly due to abnormalities in the RBCs themselves.Methods: To investigate this hypothesis, we used flow cytometry FSC/SSC to study RBCs sampled from seven patients with Gaucher disease in terms of their shape and the expression of markers of senescence and phagocytosis. Cells from two of the seven patients were evaluated before and 9 months after the start of enzyme-replacement therapy.Results: Untreated patients were found to have abnormal flow-cytometry profiles suggesting an alteration of Gaucher RBC morphology. Scanning electron microscopy confirmed this finding by revealing many abnormally shaped RBCs. Whereas there was no evidence of desialylation of membrane glycoconjugates or phosphatidylserine exposure, RBC viability (calcein-AM test) and CD47 expression were reduced. These anomalies found in RBCs sampled from two patients before treatment, were no longer present after a 9 month-long enzyme-replacement therapy.Conclusions: We report on previously overlooked alterations of Gaucher RBCs that may facilitate erythrophagocytosis in untreated patients. Their potential role in the anemia, the excess of aggregation and rheological anomalies associated with Gaucher disease must now be addressed. RBC anomalies may

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Reduced expression of CD47 during murine red blood cell (RBC) senescence and its role in RBC clearance from the circulation

Cited by 160 publications

References 24 publications

CD47 on experimentally senescent murine RBCs inhibits phagocytosis following Fcγ receptor–mediated but not scavenger receptor–mediated recognition by macrophages

CD47 on experimentally senescent murine RBCs inhibits phagocytosis following Fcγ receptor–mediated but not scavenger receptor–mediated recognition by macrophages

Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro

A cytometric study of the red blood cells in Gaucher disease reveals their abnormal shape that may be involved in increased erythrophagocytosis

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