Review
Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death

https://doi.org/10.1016/j.semcdb.2015.01.009Get rights and content

Highlights

  • Upon injury, circulating erythrocytes may enter suicidal cell death or eryptosis.

  • Most important triggers of eryptosis include enhanced cytosolic Ca2+ activity and ceramide.

  • Regulation of eryptosis involves AMPK, GK, PAK2, CK1α, JAK3, PKC, p38-MAPK.

  • Diseases with enhanced eryptosis include genetic disorders, sepsis, malaria, renal failure and hyperbilirubinemia.

  • Excessive eryptosis may lead to anemia and impaired microcirculation.

Abstract

Eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling, is stimulated by Ca2+ entry through Ca2+-permeable, PGE2-activated cation channels, by ceramide, caspases, calpain, complement, hyperosmotic shock, energy depletion, oxidative stress, and deranged activity of several kinases (e.g. AMPK, GK, PAK2, CK1α, JAK3, PKC, p38-MAPK). Eryptosis is triggered by intoxication, malignancy, hepatic failure, diabetes, chronic renal insufficiency, hemolytic uremic syndrome, dehydration, phosphate depletion, fever, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose 6-phosphate dehydrogenase deficiency, and Wilson's disease. Eryptosis may precede and protect against hemolysis but by the same token result in anemia and deranged microcirculation.

Introduction

The life span of mature circulating erythrocytes is limited by senescence and normally approaches some 100–120 days [1], [2], [3]. The senescence involves formation of hemichromes binding to and clustering of the anion exchanger protein band 3 (AE1) with subsequent attachment of complement C3 fragments and anti-band 3 immunoglobulins [4]. Upon injury, erythrocytes may be removed prior to senescence by premature suicidal death or eryptosis, which is characterized by erythrocyte shrinkage and breakdown of the cell membrane asymmetry with translocation of phosphatidylserine from the inner leaflet of the cell membrane to the erythrocyte surface [5], [6].

Eryptosis is a physiological mechanism under complex regulation. The present paper describes the cellular mechanisms governing eryptosis and lists the various clinical conditions associated with enhanced eryptosis. Several previous reviews have discussed the various aspects of suicidal erythrocyte death [6], [7], [8], [9], [10], [11], [12]. Owing to limitation of space, reviews had to be cited at several places instead of original papers.

Section snippets

Mechanisms regulating and executing eryptosis

A wide variety of conditions stimulate eryptosis, such as osmotic shock [13], energy depletion [14], oxidative stress [11], [15] or increase of temperature [16]. Both cell shrinkage and cell membrane scrambling are triggered by increase of cytosolic Ca2+ activity ([Ca2+]i) [6]. Mechanisms increasing [Ca2+]i include activation of Ca2+-permeable unselective cation channels with subsequent Ca2+ entry [6], [17]. The channels are permeable to further cations including Na+ [18]. The cation channels

Consequences of eryptosis

Phosphatidylserine at the surface of eryptotic cells binds to respective receptors of phagocytes thus leading to engulfment and subsequent degradation of the affected erythrocytes [6]. Accordingly, eryptotic erythrocytes are rapidly cleared from circulating blood [77]. As long as parallel stimulation of erythropoiesis outweighs the loss of eryptotic erythrocytes, the number of circulating erythrocytes remains constant [6]. In that case, the enhanced turnover of erythrocytes is apparent from an

Clinical conditions associated with enhanced eryptosis

A vast number of xenobiotics and endogenous substances may trigger eryptosis [6], [11], [75], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126]. Moreover, stimulated eryptosis is observed in a wide variety of clinical conditions [6] (Fig. 1).

Eryptosis is stimulated

Conclusions

Upon injury, erythroctes may enter suicidal death or eryptosis, characterized by shrinkage and cell membrane scrambling. Mechanisms involved include Ca2+-permeable, PGE2-activated cation channels, ceramide, caspases, calpain, complement activation, energy depletion, oxidative stress, and several kinases (e.g. AMPK, GK, PAK2, CK1α, JAK3, PKC, p38-MAPK). Enhanced eryptosis is triggered by diverse xenobiotics and observed e.g. in diabetes, malignancy, hyperbilirubinemia, chronic renal

Competing interest

No competing financial interests exist.

Acknowledgements

The authors acknowledge the meticulous preparation of the manuscript by Tanja Loch. Research in the authors’ laboratory was supported by the German Research Foundation.

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