Enhanced programmed cell death of iron‐deficient erythrocytes

Kempe, Daniela S.; Lang, Philipp A.; Duranton, Christophe; Akel, Ahmad; Lang, Karl S.; Huber, Stephan M.; Wieder, Thomas; Läng, Florian

doi:10.1096/fj.05-4872fje

Cited by 223 publications

(223 citation statements)

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“…A wide variety of clinical disorders is known to stimulate eryptosis, including iron deficiency [36], phosphate depletion [6], hemolytic uremic syndrome [43], sepsis [35], malaria [10,37,38], or Wilson's disease [46]. Some of these diseases may cause eryptosis by stimulating the formation of hemin.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, eryptotic cells are rapidly cleared from circulating blood [36], and stimulation of eryptosis leads to anemia, if the accelerated loss of circulating erythrocytes is not matched by a similarly increased formation of new erythrocytes. The latter is apparent from an increase in the reticulocyte number.…”

Section: Discussionmentioning

confidence: 99%

“…Eryptosis is stimulated by increase in cytosolic Ca 2+ activity [5,11,12,19,41]. Phosphatidylserine-exposing erythrocytes are engulfed by macrophages and are thus rapidly eliminated from circulating blood [24,26,36]. Cytosolic Ca 2+ concentration is increased by activation of Ca 2+ -permeable cation channels [20,21,32,41].…”

Section: Introductionmentioning

confidence: 99%

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Hemin-induced suicidal erythrocyte death

2009

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Several diseases, such as malaria, sickle cell disease, and ischemia/reperfusion may cause excessive formation of hemin, which may in turn trigger hemolysis. A variety of drugs and diseases leading to hemolysis triggers suicidal erythrocyte death or eryptosis, i.e., cell membrane scrambling and cell shrinkage. Eryptosis is elicited by increased cytosolic Ca 2+ activity and by ceramide. The present study explored whether hemin stimulates eryptosis. Cell membrane scrambling was estimated from annexin Vbinding to phosphatidylserine exposed at the cell surface, cell shrinkage from forward scatter in fluorescence-activated cell sorter analysis, cytosolic Ca 2+ activity from Fluo3 fluorescence and ceramide formation from fluorescencelabeled antibody binding. Exposure to hemin (1-10 μM) within 48 h significantly increased annexin V-binding, decreased forward scatter, increased cytosolic Ca 2+ activity, and stimulated ceramide formation. In conclusion, hemin stimulates suicidal cell death, which may in turn contribute to the clearance of circulating erythrocytes and thus to anemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hemin-induced suicidal erythrocyte death

2009

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“…54,55 Modifications in erythrophagocytosis contribute to the pathogenesis of several disorders. Increased eryptosis of erythrocytes has been described in iron deficiency, 56 in sickle cell disease, 57 or in patients with non-alcoholic steatohepatitis, 58 contributing to reduced life span of red blood cells, severity of the anemia and abnormal liver iron deposits. Activation of macrophages by cytokines and increased erythrophagocytosis are hallmarks of the anemia of chronic diseases and hemophagocytic syndrome.…”

Section: Erythrophagocytosis and Recycling Of Heme Ironmentioning

confidence: 99%

Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis

Iolascon¹,

Falco²,

Beaumont³

2009

Haematologica

133

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© F e r r a t a S t o r t i F o u n d a t i o nAIn this paper we will review the new information available on the iron acquisition pathway by developing erythrocytes and its regulation, and we will consider only inherited microcytosis due to heme synthesis or to iron metabolism defects. Iron and erythropoiesis Iron acquisition pathway in erythroid cellsDeveloping erythroid cells in the bone marrow acquire iron from the plasma iron-transferrin (Tf) complex, through the transferrin receptor (TfR) mediated pathway ( Figure 1). All proliferating cells express transferrin receptors on their cell surface at levels varying from 10 3 to 10 5 molecules per cell. Erythroid precursors, which have an extraordinary requirement for iron to allow for production of hemoglobin, may have over 10 6 transferrin receptors per cell.3 The transferrin-Fe(III) complex in plasma is transported into cells principally through transferrin receptor 1 (TfR1), which is expressed on all dividing cells and is particularly abundant on erythroid precursors. TfR2, encoded by a different gene, is expressed primarily in the liver and binds the transferrin-Fe(III) complex at a much lower affinity than TfR1 and appears to be a signaling molecule rather than an iron transporter. 4 At the pH of the cell surface, TfR1 binds only diferric transferrin. The Tf-Fe(III)/TfR1 complex is internalized into a clathrin-coated pit that, assisted by an adaptor protein complex designated AP-2, 5 rapidly matures to a proton-pumping, pH-lowering endosome. At the lowered pH, iron is released from Tf and subsequently reduced to Fe(II) and transported across the endosomal membrane by Divalent Metal Transporter 1 (DMT1).6 DMT1/Nramp2, a member of the Natural Resistance-Associated-Macrophage Protein (Nramp) family, is a proton-coupled divalent metal transporter found at the plasma membrane and in endosomes of cells of both the duodenum and peripheral tissues. Iron-depleted Tf is then returned to the cell surface where, again encountering a pH of 7.4, the protein is released for another cycle of iron transport. Recently, Steap3 (6-transmembrane epithelial antigen of the prostate 3), an endosomal ferrireductase that facilitates Tf-mediated uptake of iron in erythroid precursors has been identified. 8Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tfbound iron uptake. Erythroid cells from mice deficient in Steap3 (nm1054) are defective in Tf-dependent iron uptake, resulting in a hypochromic, microcytic anemia typical of iron deficiency 9 whereas overexpression of Steap3 stimulates the reduction of iron. Taken together, these findings indicate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells. However, nml054 and Steap3 −/− erythroid precursors retain some residual ferrireductase as well as iron uptake activity, indicating that there are other ways of reducing iron in the Tf-cycle endosome and/or that there are other endosomal iron transporters that are not res...

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“…In line with their increased cytosolic Ca 2ϩ concentration, a well known trigger of phospholipid scrambling (12), cGKI-deficient erythrocytes show increased surface exposure of PS, a hallmark of eryptosis (14,15). The exposure of PS at the erythrocyte surface mediates binding to PS receptors of macrophages (18) followed by engulfment (19) and clearance from circulating blood (32). Indeed, cGKI-deficient erythrocytes disappear faster from the circulation than ctr erythrocytes.…”

Section: Figmentioning

confidence: 99%

Anemia and splenomegaly in cGKI-deficient mice

Föller

Feil²,

Ghoreschi³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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133

115

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To explore the functional significance of cGMP-dependent protein kinase type I (cGKI) in the regulation of erythrocyte survival, gene-targeted mice lacking cGKI were compared with their control littermates. By the age of 10 weeks, cGKI-deficient mice exhibited pronounced anemia and splenomegaly. Compared with control mice, the cGKI mutants had significantly lower red blood cell count, packed cell volume, and hemoglobin concentration. Anemia was associated with a higher reticulocyte number and an increase of plasma erythropoietin concentration. The spleens of cGKI mutant mice were massively enlarged and contained a higher fraction of Ter119 ؉ erythroid cells, whereas the relative proportion of leukocyte subpopulations was not changed. The Ter119 ؉ cGKI-deficient splenocytes showed a marked increase in annexin V binding, pointing to phosphatidylserine (PS) exposure at the outer membrane leaflet, a hallmark of suicidal erythrocyte death or eryptosis. Compared with control erythrocytes, cGKI-deficient erythrocytes exhibited in vitro a higher cytosolic Ca 2؉ concentration, a known trigger of eryptosis, and showed increased PS exposure, which was paralleled by a faster clearance in vivo. Together, these results identify a role of cGKI as mediator of erythrocyte survival and extend the emerging concept that cGMP/cGKI signaling has an antiapoptotic/prosurvival function in a number of cell types in vivo.apoptosis ͉ Ca2ϩ channels ͉ phosphatidylserine ͉ spleen N itric oxide (NO) has been shown to be a powerful regulator of cell survival (1, 2). Depending on the source or concentration of NO and the influence of additional regulators, NO may stimulate or inhibit apoptosis (3). NO exerts its effects in part through S-nitrosylation of target proteins. However, the effect of NO donors on Ca 2ϩ -induced phosphatidylserine (PS) exposure, a hallmark of apoptosis, could be mimicked by cGMP analogs (4), suggesting the involvement of soluble guanylyl cyclase, cGMP, and cGMP-dependent protein kinase type I (cGKI), a well known signaling cascade downstream of NO (5, 6).Recent studies indicated that erythroid cells possess a functional NO/cGMP pathway (7-9), which may be involved in the regulation of eryptosis, the suicidal death of erythrocytes (10). Erythrocyte cGMP production might also be stimulated by NO generated in the endothelium. The cGKI can also be activated independent of cGMP in response to oxidative stress (11). Eryptosis may follow osmotic shock, energy depletion, and oxidative stress (10), which activate Ca 2ϩ -permeable cation channels (12). Subsequent Ca 2ϩ entry leads to activation of Ca 2ϩ -sensitive K ϩ channels, exit of KCl with osmotically obliged water, and thus cell shrinkage (13). In addition, Ca 2ϩ entry triggers Ca 2ϩ -sensitive scrambling of the cell membrane (14, 15) with subsequent exposure of PS at the erythrocyte surface (12). Cell membrane scrambling may further be triggered by ceramide (16) and activation of protein kinase C (17). PS-exposing erythrocytes bind to PS receptors (18) and are recognized, ...

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Enhanced programmed cell death of iron‐deficient erythrocytes

Cited by 223 publications

References 58 publications

Hemin-induced suicidal erythrocyte death

Hemin-induced suicidal erythrocyte death

Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis

Anemia and splenomegaly in cGKI-deficient mice

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