Cells in focus
Killing me softly – Suicidal erythrocyte death

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Abstract

Similar to nucleated cells, erythrocytes may undergo suicidal death or eryptosis, which is characterized by cell shrinkage, cell membrane blebbing and cell membrane phospholipid scrambling. Eryptotic cells are removed and thus prevented from undergoing hemolysis. Eryptosis is stimulated by Ca2+ following Ca2+ entry through unspecific cation channels. Ca2+ sensitivity is enhanced by ceramide, a product of acid sphingomyelinase. Eryptosis is triggered by hyperosmolarity, oxidative stress, energy depletion, hyperthermia and a wide variety of xenobiotics and endogenous substances. Eryptosis is inhibited by nitric oxide, catecholamines and a variety of further small molecules. Erythropoietin counteracts eryptosis in part by inhibiting the Ca2+-permeable cation channels but by the same token may foster formation of erythrocytes, which are particularly sensitive to eryptotic stimuli. Eryptosis is triggered in several clinical conditions such as iron deficiency, diabetes, renal insufficiency, myelodysplastic syndrome, phosphate depletion, sepsis, haemolytic uremic syndrome, mycoplasma infection, malaria, sickle-cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase-(G6PD)-deficiency, hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria, and Wilson's disease. Enhanced eryptosis is observed in mice with deficient annexin 7, cGMP-dependent protein kinase type I (cGKI), AMP-activated protein kinase AMPK, anion exchanger AE1, adenomatous polyposis coli APC and Klotho as well as in mouse models of sickle cell anemia and thalassemia. Eryptosis is decreased in mice with deficient phosphoinositide dependent kinase PDK1, platelet activating factor receptor, transient receptor potential channel TRPC6, janus kinase JAK3 or taurine transporter TAUT. If accelerated eryptosis is not compensated by enhanced erythropoiesis, clinically relevant anemia develops. Eryptotic erythrocytes may further bind to endothelial cells and thus impede microcirculation.

Introduction

In healthy individuals, the erythrocyte number exceeds 4 × 1012/l circulating blood (Jelkmann, 2012). The erythrocyte life span approaches usually 100–120 days (Jelkmann, 2012). Thus, in an individual with 5 l of blood, more than 1011 erythrocytes are newly formed and removed each single day. Erythrocyte life span is limited by senescence with subsequent clearance of the aged erythrocytes [for references see Jelkmann, 2012]. During senescence binding of modified hemoglobins to band 3 is followed by modification of band 3, binding of autologous IgG, disruption of the band 3-mediated anchorage of the cytoskeleton to the lipid bilayer, and generation of vesicles exposing senescent cell antigens and phosphatidylserine, which are subsequently bound to scavenger receptors [for references see Lang et al., 2010b].

Prior to senescence, erythrocytes may experience injury, which may compromise their integrity and survival. Under this condition the affected erythrocyte may undergo suicidal death or eryptosis [for references see Lang et al., 2010b]. Similar to suicidal death of nucleated cells or apoptosis, eryptosis is a coordinated, programmed cell death eventually leading to disposal of defective cells without rupture of the cell membrane and release of intracellular material [for references see Lang et al., 2010b]. Thus, in contrast to hemolysis, eryptosis is a “soft” mechanism eliminating defective erythrocytes prior to hemolysis.

In contrast to nucleated cells, erythrocytes lack nuclei and mitochondria (Jelkmann, 2012), important organelles in the machinery underlying suicidal death of nucleated cells or apoptosis (Wlodkowic et al., 2011). Accordingly, eryptosis lacks several hallmarks of apoptosis, such as mitochondrial depolarization and condensation of nuclei. Accordingly, the signaling underlying suicidal erythrocyte death is lacking important elements (Lang et al., 2010b) effective in apoptosis of nucleated cells (Wlodkowic et al., 2011). Eryptosis shares, however, other hallmarks of apoptosis, such as cell shrinkage, cell membrane blebbing and cell membrane scrambling leading to phosphatidylserine exposure at the cell surface [for references see Lang et al., 2010b]. Similar to apoptotic cells and particles, eryptotic cells are recognized by macrophages, engulfed and degraded [for references see Lang et al., 2010b]. Thus, it appears appropriate to conclude that eryptosis serves the same purpose of apoptosis, i.e. the removal of defective, infected or otherwise potentially harmful cells. In the past decades apoptosis has been extensively studied and the complex machinery has been elucidated in great detail (Wlodkowic et al., 2011). Knowledge on eryptosis is rather limited and much is still to be learned about the mechanisms involved in the triggering of suicidal erythrocyte death.

The present review describes the mechanisms triggering and inhibiting suicidal erythrocyte death or eryptosis. Prior to that erythrocyte origin and plasticity, erythrocyte functions and pathologies associated with eryptosis will briefly be described. Due to limitation of references, preference is given to recent papers on eryptosis. The reader may find earlier references in a previous review (Lang et al., 2010b). The authors do hope that the present treatise fosters additional experimental effort to fully unravel the machinery underlying this important physiological mechanism.

Section snippets

Erythrocyte origin and plasticity

Erythrocytes are produced in embryonic yolk sac, fetal liver, fetal spleen and fetal as well as adult red bone marrow (Jelkmann, 2012). The erythrocytes originate from pluripotent hemopoietic stem cells, which develop into erythrocytic progenitor cells. Several stages of differentiation and maturation including loss of nuclei and mitochondria lead to the formation erythroblasts, normoblasts and eventually reticulocytes, which are released into circulating blood and within 1–2 days develop into

Erythrocyte functions

The most important function of circulating erythrocytes is the transport of O2 from lung to tissues. Moreover, erythrocytes are further essential for the adequate transport of CO2 in blood from tissues to lung [for references see Jelkmann, 2012]. Erythrocytes decrease the vascular tone by releasing ATP and NO [for references see Jelkmann, 2012]. The ATP release is triggered by shear stress in narrow vessels. NO is bound to oxygenated hemoglobin and is released following desoxygenation of

Associated pathologies: anemia and deranged microcirculation

The most important pathology of erythocytes is anemia, which compromizes O2 transport in blood [for references see Jelkmann, 2012]. On the other hand, abnormally high numbers of erythrocytes increases the blood viscosity and the risk to develop thrombosis [for references see Jelkmann, 2012] Consequences may include heart failure, myocardial infarction, peripheral thromboses, pulmonary embolism and seizures [for references see Jelkmann, 2012].

Both, anemia and thrombosis may result from excessive

Mechanisms triggering eryptosis

Triggers of eryptosis include increase of cytosolic Ca2+ activity, which may result from increased Ca2+ entry [for references see Lang et al., 2010b] (Fig. 1). Ca2+ may enter following activation of Ca2+ permeable non-selective cation channels. The molecular identity of the cation channels remained enigmatic but is considered to involve TRPC6 [for references see Lang et al., 2010b]. Accordingly, Ca2+ entry is blunted in the presence of antibodies directed against TRPC6 and in erythrocytes drawn

The physiological significance of eryptosis

Eryptosis accomplishes the removal of defective erythrocytes, which would otherwise die from hemolysis, a necrosis-like death. Hemolysis is fostered by energy depletion, impaired function of Na+/K+-ATPase or enhanced leakiness of the cell membrane, which all are followed by cellular gain of Na+ and Cl together with osmotically obliged water thus leading to cell swelling [for references see Lang et al., 2010b]. Excessive cell swelling may lead to rupture of the cell membrane with release of

Diseases associated with enhanced eryptosis

A variety of clinical disorders are associated with excessive eryptosis (Table 3). Enhanced eryptosis is observed in iron deficiency, whereby the decreased erythrocyte volume presumably contributes to the enhanced susceptibility to eryptosis, as detailed above. Eryptosis is further enhanced in diabetes and renal insufficiency (Table 3). The eryptosis is in those clinical conditions at least in part due to accumulation of toxic substances such as methylglyoxal (Table 1).

Eryptosis is triggered by

References (45)

  • O. Borst et al.

    Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/SR-PSOX

    American Journal of Physiology: Cell Physiology

    (2012)
  • J.V. Calderon-Salinas et al.

    Eryptosis and oxidative damage in type 2 diabetic mellitus patients with chronic kidney disease

    Molecular and Cellular Biochemistry

    (2011)
  • S.K. Dasgupta et al.

    Role of lactadherin in the clearance of phosphatidylserine-expressing red blood cells

    Transfusion

    (2008)
  • M. Eberhard et al.

    FTY720-induced suicidal erythrocyte death

    Cellular Physiology and Biochemistry

    (2010)
  • M. Eberhard et al.

    Effect of phytic acid on suicidal erythrocyte death

    Journal of Agricultural and Food Chemistry

    (2010)
  • K.M. Felder et al.

    Hemotrophic mycoplasmas induce programmed cell death in red blood cells

    Cellular Physiology and Biochemistry

    (2011)
  • M. Foller et al.

    Suicide for survival – death of infected erythrocytes as a host mechanism to survive malaria

    Cellular Physiology and Biochemistry

    (2009)
  • M. Foller et al.

    Temperature sensitivity of suicidal erythrocyte death

    European Journal of Clinical Investigation

    (2010)
  • M. Foller et al.

    Endothelin B receptor stimulation inhibits suicidal erythrocyte death

    FASEB Journal

    (2010)
  • S. Gatidis et al.

    Phlorhizin protects against erythrocyte cell membrane scrambling

    Journal of Agricultural and Food Chemistry

    (2011)
  • S. Gatidis et al.

    p38 MAPK activation and function following osmotic shock of erythrocytes

    Cellular Physiology and Biochemistry

    (2011)
  • M. Ghashghaeinia et al.

    Targeting glutathione by dimethylfumarate protects against experimental malaria by enhancing erythrocyte cell membrane scrambling

    American Journal of Physiology: Cell Physiology

    (2010)
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