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American Journal of Clinical Nutrition, Vol. 87, No. 5, 1530-1534, May 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Zinc-induced suicidal erythrocyte death1,2,3

Valentin Kiedaisch, Ahmad Akel, Olivier M Niemoeller, Thomas Wieder and Florian Lang

1 From the Departments of Physiology (VK, AA, OMN, TW, and FL), Dermatology (TW), and Radiation Oncology (OMN), University of Tübingen, Tübingen, Germany

2 Supported by the Deutsche Forschungsgemeinschaft, Nr. La 315/4–3, LA 315/6–1 and La 315/13–1.

3 Address reprint requests and correspondence to F Lang, Physiologisches Institut der Universität Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany. E-mail: florian.lang{at}uni-tuebingen.de.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Zn2+ stimulates secretory sphingomyelinase, which in turn produces ceramide, an important trigger of suicidal erythrocyte death or eryptosis. Eryptosis is characterized by exposure of phosphatidylserine (PS) at the erythrocyte surface and by cell shrinkage. As macrophages are equipped with PS receptors, they bind, engulf, and degrade PS-exposing cells.

Objective: We examined whether Zn2+ stimulates ceramide formation and PS exposure of erythrocytes and thus may be able to trigger suicidal erythrocyte death.

Design: In erythrocytes from healthy volunteers, PS exposure (Annexin V binding), cell volume (forward scatter), cytosolic Ca2+ activity (Fluo3 fluorescence), and ceramide formation (anticeramide antibody) were determined by fluorescence-assisted cell sorting.

Results: Exposure to Zn2+ (≥25 µmol/L Zn2+) significantly increased annexin binding. The effect was paralleled by increase of cytosolic Ca2+ activity (≥25 µmol/L Zn2+) and by ceramide formation (≥10 µmol/L Zn2+). Glucose depletion (24 h) similarly increased PS exposure, an effect significantly enhanced in the presence of Zn2+ (≥10 µmol/L Zn2+).

Conclusion: Zn2+ triggers suicidal erythrocyte death, an effect partially due to ceramide formation and an increase of cytosolic Ca2+ activity.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Zinc, an essential nutrient, counteracts a variety of infectious diseases (1, 2) including malaria (3), diarrhea (3, 4), and respiratory infections (3, 5, 6). Zinc supplementation is considered particularly important in infants and children (7-10), pregnant women (11), and the elderly (12) and has proven beneficial in healing burns (13).

Ionic zinc (Zn2+), a concentrated liquid supplement, has been shown to activate a secretory sphingomyelinase leading to the formation of ceramide (14). The pleotropic effects of ceramide include triggering of suicidal erythrocyte death (15), or eryptosis (16), which is characterized by exposure of phosphatidylserine at the erythrocyte surface (17, 18). Because macrophages are equipped with receptors specific for phosphatidylserine (19), erythrocytes exposing phosphatidylserine at their surface will be rapidly recognized, engulfed, and degraded (20) and are thus expected to be rapidly eliminated from circulating blood.

Erythrocyte phosphatidylserine exposure is accomplished by cell membrane scrambling (21, 22), which is triggered by an increase of the cytosolic Ca2+ activity (17). The Ca2+ sensitivity of phospholipid scrambling is enhanced by ceramide (15). The increased Ca2+ activity may result from activation of Ca2+-permeable cation channels, which are activated by osmotic shock, oxidative stress, and energy depletion (23). In addition to cell membrane scrambling, Ca2+ activates Ca2+-sensitive K+ channels (24, 25), which leads to the exit of KCl with osmotically obliged water and thus to cell shrinkage (26).

Enhanced eryptosis parallels several anemic conditions such as sickle cell disease, thalassemia, glucose-phosphate dehydrogenase deficiency, phosphate depletion, iron deficiency (27), hemolytic uremic syndrome, sepsis, malaria, and Wilson's disease (16, 27, 28). Beyond that, eryptosis may be triggered by methylglyoxal (29), amyloid (30), listeriolysin (31), paclitaxel (32), chlorpromazine (33), cyclosporine (34), lead (35), and mercury (36). Eryptosis has similarities to, but may be distinct from, erythrocyte senescence (16).

Accelerated eryptosis has been shown to protect against a severe course of malaria (37, 38).

The present experiments were designed to test the hypothesis that Zn2+ ions could stimulate ceramide formation in erythrocytes and that the stimulation of ceramide formation may lead to stimulation of phosphatidylserine exposure. Thus, the present experiments were performed to explore whether exposure to Zn2+ ions triggers phosphatidylserine exposure and to elucidate the underlying mechanisms.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This study was approved by the local ethics committee of the University of Tübingen (project#: 184/2003V).

Erythrocytes and solutions
Blood was drawn from 9 healthy adult volunteers (not known to the authors) at the Blutspendezentrale Tübingen (http://www.blutspendezentrale.de/), and erythrocyte concentrates were prepared with the use of leukocyte depletion filters as described (39). Aliquots of the individual erythrocyte concentrates were either used directly in the independent experiments or stored at 4°C until usage. Experiments were performed at 37°C in Ringer solution containing 125 mmol/L NaCl, 5 mmol/L KCl, 1 mmol/L MgSO4, 32 mmol/L N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES)/NaOH (pH 7.4), 5 mmol/L glucose, and 1 mmol/L CaCl2. Zinc chloride (Sigma, Taufkirchen, Germany) was added to the Ringer solution at final concentrations varying from 1 to 50 µmol/L.

Fluorescence-assisted cell sorting
Fluorescence-assisted cell sorting (FACS) analysis was performed as described (39). After incubation in the presence or absence of Zn2+ ions, cells were washed in annexin-binding buffer containing 125 mmol/L NaCl, 10 mmol/L HEPES/NaOH (pH 7.4), and 5 mmol/L CaCl2. Erythrocytes were suspended in a solution composed of Annexin-V-Fluos (Roche Diagnostics, Mannheim, Germany) and annexin-binding buffer (dilution of 1:50). After 10 min of incubation, samples were finally diluted 1:5 in annexin-binding buffer and measured by flow cytometric analysis on a FACS-Calibur from Becton Dickinson (Heidelberg, Germany). Cells were analyzed by forward scatter, and annexin-fluorescence intensity was measured in the fluorescence channel FL-1 with an excitation wavelength of 488 nm and an emission wavelength of 530 nm.

Measurement of intracellular Ca2+
Intracellular Ca2+ measurements were performed as described (23). Briefly, erythrocytes were washed in sodium-chloride Ringer solution and then loaded with Fluo-3/AM (Calbiochem; Bad Soden, Germany) in 2 mmol/L CaCl2- and 2 µmol/L Fluo-3/AM-containing sodium-chloride Ringer solution. The cells were incubated at 37°C for 20 min under shaking condition and washed twice in 2 mmol/L CaCl2-containing sodium-chloride Ringer solution. The Fluo-3/AM-loaded erythrocytes were resuspended in 200 µL Ringer solution in the presence or absence of Zn2+. Then, Ca2+-dependent fluorescence intensity was measured in the fluorescence channel FL-1 with an excitation wavelength of 488 nm and an emission wavelength of 530 nm. As an exposure time of 24 h would result in considerable loss of fluorescent dye, exposure time was restricted to 6 h.

Determination of ceramide formation
Cells were stained for 1 h at 4°C with anticeramide antibody or isotype-matched pure mouse antibody in phosphate-buffered saline (PBS) containing 1% fetal calf serum (FCS) at a dilution of 1:5 as described recently (39). After 3 washes with PBS/1% FCS, cells were stained with polyclonal fluorescein isothiocyanate (FITC)-conjugated goat anti-mouse Ig-specific antibody (Pharmingen, Hamburg, Germany) in PBS/1% FCS at a dilution of 1:50 for 30 min. Unbound secondary antibody was removed by washing the cells 2 times with PBS/1% FCS, and samples were analyzed by flow cytometric analysis on a FACS-Calibur. FITC-fluorescence intensity was measured in the fluorescence channel FL-1. As a positive control, erythrocytes were treated for 5 min with 0.1 unit/mL Streptomyces sp. sphingomyelinase from Sigma.

Statistics
Because of the large variation in the sensitivity of the individual erythrocyte concentrates, all data are expressed as arithmetic means ± SEM, and the number of independent experiments using blood from different donors is stated. Statistical analysis was made by ANOVA using Dunnett's test as post hoc test (GRAPHPAD INSTAT; GraphPad Software Inc, San Diego, CA). P < 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Incubation of freshly drawn erythrocytes in Ringer solution for 24 h resulted in low but appreciable phosphatidylserine exposure with subsequent annexin binding in 4.1 ± 0.5% (n = 9) of the cells. Addition of Zn2+ (Zn2+ concentrations varying from 1 to 50 µmol/L) to the Ringer solution significantly increased the percentage of annexin-binding cells in a dose-dependent manner (Figure 1Go, A and B).


Figure 1
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  		FIGURE 1.. Stimulation of phosphatidylserine exposure at the erythrocyte surface by Zn2+. A) Histograms of annexin binding in a representative experiment of erythrocytes incubated for 24 h in Ringer solution (left panel), or in Ringer solution containing 25 µmol/L Zn2+ ions (right panel). The numbers indicate the percentage of annexin-binding erythrocytes of the respective cell population as confined by the horizontal line. B) Arithmetic means ± SEM (n = 9) of annexin binding erythrocytes after 24-h treatment with Ringer solution as a function of the Zn2+ concentration. *Significant difference (ANOVA using Dunnett's test as post hoc test, P < 0.05) from absence of Zn2+ ions (Ringer solution, white bar).

 
The effect of Zn2+ on annexin binding was paralleled by a decrease of the forward scatter reflecting erythrocyte shrinkage (Figure 2Go, A and B). The effect of Zn2+ was dependent on the Zn2+ concentration and achieved statistical significance at 25 µmol/L Zn2+ (Figure 2BGo).


Figure 2
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  		FIGURE 2.. Erythrocyte shrinkage following exposure to Zn2+. A) Histograms of forward scatter in a representative experiment of erythrocytes incubated for 24 h in Ringer solution (left panel), or in Ringer solution containing 25 µmol/L Zn2+ ions (right panel). The numbers indicate the GeoMean of the forward scatter of the respective cell population. B) Arithmetic means ± SEM, (n = 9) of forward scatter of erythrocytes after a 24-h treatment with Ringer solution as a function of the Zn2+ concentration. *Significant difference (ANOVA using Dunnett's test as post hoc test, P < 0.05) from absence of Zn2+ ions (Ringer solution, white bar).

 
As illustrated in Figure 3Go, exposure to Zn2+ for 6 h increased cytosolic Ca2+. The effect was statistically significant at 25 µmol/L Zn2+.


Figure 3
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  		FIGURE 3.. Increase of cytosolic Ca2+ activity in erythrocytes following exposure to Zn2+. A) Histograms of Fluo3 fluorescence in a representative experiment of erythrocytes exposed for 6 h to Ringer solution without (left panel) and with (right panel) 50 µmol/L Zn2+. The numbers indicate the mean fluorescence of erythrocytes of the respective cell population. B) Arithmetic means ± SEM (n = 4) of Fluo3 fluorescence in erythrocytes exposed for 6 h to Ringer solution without Zn2+ (white bar) and with 10 µmol/L Zn2+ (light gray bar), 25 µmol/L Zn2+ (dark gray bar), or 50 µmol/L Zn2+ (black bar). *Significant difference to value in absence of Zn2+ (ANOVA using Dunnett's test as post hoc test, P < 0.05).

 
As illustrated in Figure 4Go, exposure of erythrocytes to Zn2+ (≥10 µmol/L) led within 24 h to a significant increase of ceramide formation. Bacterial sphingomyelinase, utilized as positive control, similarly increased ceramide formation (Figure 4Go, A and B).


Figure 4
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  		FIGURE 4.. Stimulation of ceramide formation in erythrocytes following exposure to Zn2+. A) One-dimensional flow cytometry histograms of anticeramide fluorescein isothiocyanate (FITC)-coupled antibody binding (x axis) in a representative experiment of erythrocytes incubated for 24 h in Ringer solution without (control, left panel), or with 25 µmol/L Zn2+ (Zn2+, middle panel) or for 5 min in Ringer solution containing 0.1 U/mL sphingomyelinase (SMase, right panel). The numbers indicate the GeoMean of anticeramide FITC binding of the respective cell population. B) Anticeramide FITC-coupled antibody binding (arithmetic means ± SEM; n = 6) of erythrocytes after incubation for 24 h in Ringer solution without Zn2+ (left, open bar), with 10 µmol/L Zn2+ (left, gray bar) or with 25 µmol/L Zn2+ (left, black bar), or for 5 min in the absence (right, white bar) or presence (right, black bar) of 0.1 U/mL SMase) in Ringer solution. *Significant difference to the value in absence of Zn2+ (ANOVA using Dunnett's test as post hoc test, P < 0.05).

 
Exposure of erythrocytes to glucose depletion resulted in the expected (40) increase of phosphatidylserine exposure (Figure 5Go A; compare the upper left histogram with the lower left histogram). The increase of phosphatidylserine exposure after glucose removal was significantly enhanced in the presence of Zn2+ (≥10 µmol/L) (Figure 5BGo). Thus, Zn2+ and energy depletion mutually enhance the susceptibility of erythrocytes to undergo eryptosis.


Figure 5
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  		FIGURE 5.. Stimulation of phosphatidylserine exposure at the erythrocyte surface by glucose depletion in the absence and presence of Zn2+. A) Histograms of annexin binding in a representative experiment of erythrocytes incubated for 24 h in Ringer solution (upper panels) or in glucose-free Ringer solution (lower panels) in the absence (left panels) and in the presence (right panels) of 25 µmol/L Zn2+. The numbers indicate the percentage of annexin-binding erythrocytes of the respective cell population as confined by the horizontal line. B) Arithmetic means ± SEM (n = 4) of annexin binding of erythrocytes after 24-h treatment with glucose-free Ringer solution (0Glc) in the absence of Zn2+ (white bar) or in the presence of 10 µmol/L Zn2+ (gray bar) or 25 µmol/L Zn2+ (black bar). *Significant difference (ANOVA using Dunnett's test as post hoc test, P < 0.05) from the absence of Zn2+ ions (glucose-free Ringer solution, white bar).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present experiments disclose a novel action of Zn2+ on erythrocytes. The trace element triggers erythrocyte cell membrane phospholipid scrambling leading to phosphatidylserine exposure at the cell membrane surface. The effect of Zn2+ is paralleled by erythrocyte shrinkage, another typical feature of eryptosis (16). Similarly, cell shrinkage is a hallmark of apoptosis of nucleated cells (41).

The effects are at least partially due to increased cytosolic Ca2+ activity, which is known to stimulate phospholipid scrambling of the cell membrane (17, 18) and to activate Ca2+-sensitive K+ channels (24, 25). The K+ exit through those channels leads to hyperpolarization of the cell membrane, which drives Cl– toward the extracellular space. The combined exit of K+, Cl–, and osmotically obliged water then leads to cell shrinkage.

The effect is, further, the result of ceramide formation. Previous studies revealed the ability of Zn2+ to activate a ceramide-producing secretory sphingomyelinase (14). Ceramide, in turn, sensitizes erythrocytes for the scrambling effect of Ca2+ (15).

Exposure to Zn2+ further sensitizes the cell for the scrambling effect of energy depletion. Previous studies (40) have shown that energy depletion leads to activation of protein kinase C, which in turn triggers cell membrane scrambling.

The effect of Zn2+ requires Zn2+ concentrations in the range of those encountered in human plasma (42). Thus, excessive intake of Zn2+ could well trigger suicidal death of circulating erythrocytes. Thus, the observed effects of Zn2+ could indeed be relevant for in vivo conditions.

Phosphatidylserine-exposing cells are bound to respective receptors on macrophages (19), leading to engulfment and subsequent degradation (20). Accordingly, phosphatidylserine-exposing erythrocytes are rapidly cleared from circulating blood (27). Thus, at least in theory, the stimulation of suicidal death of circulating erythrocytes could cause anemia. Side effects of Zn2+ excess indeed include anemia (43, 44), an effect, however, in large part attributed to copper deficiency (45). During malaria, on the other hand, enhanced susceptibility to eryptosis could foster the elimination of infected erythrocytes and thus protect against a severe course of the disease (37, 38). Additional studies are required, however, to test whether the beneficial effect of zinc supplementation in malaria (1-3) is indeed related to accelerated eryptosis.

Zn2+ has previously been shown to induce (46-48) and to counteract (49) apoptosis of nucleated cells. The mechanisms effective in erythrocytes may similarly participate in the regulation of nucleated cell death.

In conclusion, exposure to Zn2+ leads to phosphatidylserine exposure of erythrocytes. The effect is at least partially due to increased cytosolic Ca2+ activity and ceramide formation. In vivo, the effects could lead to accelerated clearance of phosphatidsylserine-exposing erythrocytes and thus to development of anemia.


   ACKNOWLEDGMENTS
 
We acknowledge the technical assistance of E. Faber and the meticulous preparation of the manuscript by Jasmin Bühringer and Eva Unertl.

The authors' responsibilities were as follows—VK: designed the study, and analyzed and interpreted the data; FL: wrote the manuscript; FL and TW: contributed to the analysis and interpretation of data; TW: contributed to writing the manuscript; and VK, AA and OMN: contributed to the collection of data. All authors reviewed the manuscript. None of the authors had a conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication October 26, 2007. Accepted for publication January 9, 2008.





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