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Eryptosis: an Erythrocyte's Suicidal Type of Cell Death

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Eryptosis: an Erythrocyte's Suicidal Type of Cell Death Hindawi BioMed Research International Volume 2018, Article ID 9405617, 10 pages https://doi.org/10.1155/2018/9405617 Review Article Eryptosis: An Erythrocyte’s Suicidal Type of Cell Death Lisa Repsold and Anna Margaretha Joubert Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa Correspondence should be addressed to Anna Margaretha Joubert; [email protected] Received 16 October 2017; Accepted 14 December 2017; Published 3 January 2018 Academic Editor: Christophe Duranton Copyright © 2018 Lisa Repsold and Anna Margaretha Joubert. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Erythrocytes play an important role in oxygen and carbon dioxide transport. Although erythrocytes possess no nucleus or mitochondria, they fulfl several metabolic activities namely, the Embden-Meyerhof pathway, as well as the hexose monophosphate shunt. Metabolic processes within the erythrocyte contribute to the morphology/shape of the cell and important constituents are being kept in an active, reduced form. Erythrocytes undergo a form of suicidal cell death called eryptosis. Eryptosis results from a wide variety of contributors including hyperosmolarity, oxidative stress, and exposure to xenobiotics. Eryptosis occurs before the erythrocyte has had a chance to be naturally removed from the circulation afer its 120-day lifespan and is characterised by the presence of membrane blebbing, cell shrinkage, and phosphatidylserine exposure that correspond to nucleated cell apoptotic 2+ characteristics. Afer eryptosis is triggered there is an increase in cytosolic calcium (Ca ) ion levels. Tis increase causes activation 2+ + of Ca -sensitive potassium (K ) channels which leads to a decrease in intracellular potassium chloride (KCl) and shrinkage of the erythrocyte. Ceramide, produced by sphingomyelinase from the cell membrane’s sphingomyelin, contributes to the occurrence of eryptosis. Eryptosis ensures healthy erythrocyte quantity in circulation whereas excessive eryptosis may set an environment for the clinical presence of pathophysiological conditions including anaemia. 1. Introduction which, in turn, is fltered through the kidneys and clusters in the acidic lumen of the renal tubules ultimately leading to Erythrocytes are derived from haematopoietic stem cells in renal failure [2, 3]. the red bone marrow by the production of a cytokine erythro- Erythrocytes circulate the body for approximately 120 poietin produced in the kidneys [1]. Te reticulocyte formed days before they are removed from the circulatory system from these stem cells, following a number of diferentiation by the process of senescence. Under certain conditions, steps, enters the blood stream from the bone marrow and erythrocytes undergo a form of cell death, namely, eryptosis, afer a few days in circulation it becomes a mature erythrocyte before they reach their full lifespan [4]. Tis type of cell characterised by the absence of its mitochondria and nucleus death may be caused by an injury to the erythrocyte and [1]. may be triggered by a wide variety of factors ranging from Erythrocytes are responsible for the distribution of oxy- hyperosmolarity, oxidative stress, energy depletion, heavy gen to body tissues and for transportation of carbon dioxide metal exposure, xenobiotics and antibiotics administered for to the lungs. Te pigment haemoglobin in the erythrocyte various clinical conditions [2]. facilitates binding of oxygen and carbon dioxide and delivery Characteristics of eryptosis are similar to that of apop- of oxygen to tissues [1, 2]. tosis since this type of cell death also displays comparable Erythrocytes are constantly transported through areas of hallmarks, namely, cell shrinkage, membrane blebbing, and stress. Tese areas include the lungs where the erythrocyte exposure of phosphatidylserine on the cell membrane [5]. Eryptosis is primarily caused by an increase in cytosolic is exposed to oxidative stress or through the kidneys where 2+ the erythrocyte is exposed to osmotic shock. Subsequently calcium (Ca ) ion levels during oxidative stress and osmotic 2+ the erythrocyte membrane can be detrimentally afected. Tis shock [6–8]. Ca ions enter the erythrocyte through nonse- may lead to the release of haemoglobin into extracellular fuid lective cation channels which are stimulated by prostaglandin 2 BioMed Research International Hyperosmotic stress ＃Ｆ− removal ０＇％2 Catecholamines Adenosine Erythropoeitin 2+ ＃； Glucose depletion Iron defciency COX AA ROS Plasmodia Hyperosmotic stress PLA Calpain PAF SM Ceramide NO ＃Ｆ− SCR Phosphatidylserine （2／ exposure ＋+ Figure 1: Diagram illustrating eryptosis signalling. Injury to erythrocytes activates the release of prostaglandin E2 (PGE2), which, in turn, 2+ 2+ 2+ activates the Ca cation channels increasing the infux of Ca ions into the erythrocyte and activating Ca -sensitive scramblase. Te latter causes exposure of phosphatidylserine on the cell membrane. All this leads to the formation of the characteristics of eryptosis including membrane blebbing and cell shrinkage. NO: nitric oxide, PAF: platelet activating factor, ROS: reactive oxygen species, COX: cyclooxygenase, PLA: phospholipase A2,SCR:scramblase,andPGE2: prostaglandin E2 [adapted from [11]]. 2+ + E2 and by stimulators of eryptosis that trigger cell membrane increases the presence of the Ca -sensitive K channels (Fig- 2+ vesiculation. Te increase of Ca ion levels leads to the ure 1) [2]. Ceramide is common in the presence of osmotic 2+ + activation of Ca -sensitive potassium (K )channels,also shock since it stimulates release of PAF by the activation called the Gardos channels, ultimately resulting in the loss of ofphospholipaseand,asaresultoftheceramideonthe water as it osmotically follows the loss of potassium chloride cell membrane, PAF produces a scrambled sarcolemma that (KCl) from the erythrocyte. Cell shrinkage in eryptosis results leads to exposure of phosphatidylserine on the erythrocyte 2+ + from activation of Ca -sensitive K channels leading to membrane. Tis efect of ceramide may result from the fact a loss of KCl from the erythrocyte ensued by the loss of that ceramide induces transbilayer lipid movement [2]. water [9]. Tis eventually leads to the characteristic eryptotic Additional signalling molecules related to energy deple- cell shrinkage found in suicidal erythrocytes [9–12]. Cell tion further contribute to eryptosis. Janus-activated kinase 3 membrane blebbing results from the activation of cysteine (JAK3), a transcription factor of critical tyrosine regulatory endopeptidase calpain, which functions by causing degrada- sites, is phosphorylated at tyrosine 980 (Tyr 980) [16, 17]. tion of the erythrocyte’s cytoskeleton [13–15]. Activation of JAK3 ensuing from energy depletion results in − With the loss of Cl ions there is a discharge of scrambling of the cell membrane. Furthermore, casein kinase 2+ 1� (CK1�) is pharmacologically implicated in the increase prostaglandin E2 which also increases the Ca ion levels 2+ which prompts exposure of phosphatidylserine on the cell of Ca ions and the consequent stimulation of eryptosis membrane [3]. Exposure of phosphatidylserine is caused by following exposure to oxidative stress or energy depletion in the phospholipid scrambling of the cell membrane. Once erythrocytes [16, 17]. Activation of CK1�,resultingfromphar- 2+ exposure of the phosphatidylserine on the erythrocyte takes macological stimulation, triggers entry of Ca into the ery- placeitisrecognizedbycirculatingmacrophageswithspe- throcyte through CK1�-opening of cation channels [16, 17]. cifc phosphatidylserine receptors and engulfed to ensure Eryptosis functions as a protective mechanism in some removal of the erythrocyte from the circulation [7, 8, 10]. cases, since it provides the erythrocyte with another form Cell shrinkage also causes the liberation of platelet of erythrocyte cell death other than haemolysis. Haemolysis activating factor (PAF). PAF plays a role in the control of injured or damaged erythrocytes is known to lead to the mechanism of infammation and stimulates ceramide to be release of the contents of the erythrocyte into the blood released by the disruption of sphingomyelin via the action of stream, including haemoglobin that may lead to renal failure sphingomyelinase either present in the erythrocyte or acting [16, 17]. Eryptosis is thus an efective form of erythrocyte from outside. As it is released into the plasma, ceramide cell death since it prevents erythrocytes from undergoing BioMed Research International 3 haemolysis and the complications attributed to this form clearance of injured erythrocytes. Tis corresponds with of erythrocyte cell death. Homeostasis between eryptotic the immune system’s response to antigen A in the case and antieryptotic mechanisms is vital to maintain normal of autoimmune diseases or in the case of an ABO blood erythrocyte count in the blood thereby preventing irregular- transplant [28]. ities. Anaemia ensues in instances where increased eryptosis Erythrocytes are thus more sensitive to eryptosis than results in the loss of circulating erythrocytes without accom- previously thought, even though they enter a hyperosmotic panying increase of erythropoiesis and sustaining increase of environment in the kidneys and are continuously subjected reticulocytes [16, 17]. to oxidative stress
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