Our study is highlightingoverlooked molecular interactions between erythrocytes and immunity and metabolism, whichcould lead to the discovery of potent therapeutic targets for immunometa
Trang 1Endocrine, Metabolic & Immune Disorders -Drug Targets
ISSN: 1871-5303 eISSN: 2212-3873
Impact Factor: 1.973
The official journal of the ITALIAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, shortly defined AME (Associazione Medici Endocrinologi)
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2021, 21, 843-853
REVIEW ARTICLE
Immune and Metabolic Interactions of Human Erythrocytes: A Molecular Perspective
Charalampos Papadopoulos1, Maria Panopoulou1, Konstantinos Anagnostopoulos1,* and
Ioannis Tentes1
1
Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
A R T I C L E H I S T O R Y
Received: August 08, 2020
Revised: September 15, 2020
Accepted: September 24, 2020
DOI:
10.2174/1871530320666201104115016
Abstract: Apart from their main function as oxygen carriers in vertebrates, erythrocytes are also
in-volved in immune regulation By circulating throughout the body, the erythrocytes are exposed and interact with tissues that are damaged as a result of a disease In this study, we summarize the litera-ture regarding the contribution of erythrocytes to immune regulation and metabolism Under the cir-cumstances of a disease state, the erythrocytes may lose their antioxidant capacity and release Dam-age Associated Molecular Patterns, resulting in the regulation of innate and adaptive immunity In addition, the erythrocytes scavenge and affect the levels of chemokines, circulating cell-free
mtD-NA, and C3b attached immune complexes Furthermore, through surface molecules, erythrocytes control the function of T lymphocytes, macrophages, and dendritic cells Through an array of en-zymes, red blood cells contribute to the pool of blood’s bioactive lipids Finally, the erythrocytes contribute to reverse cholesterol transport through various mechanisms Our study is highlighting overlooked molecular interactions between erythrocytes and immunity and metabolism, which could lead to the discovery of potent therapeutic targets for immunometabolic diseases.
Keywords: Erythrocytes, immunity, metabolism, lipid signaling, reverse cholesterol transport, cytokine signaling, DAMP
bind-ing, DAMP release, cellular interactions
1 INTRODUCTION
Inflammation represents a highly evolutionarily
conserved set of cellular and molecular events aiming to
re-duce the tissue damage or infection that initiated
inflamma-tion The main purpose is to clear necrotic cells, rehabilitate
the tissue damage, and elicit a tissue repair mechanism
How-ever, unless the process of inflammation resolution starts,
chronic inflammation drives further tissue damage and
fibro-sis The main molecular players of inflammation are damage
(lipopolysaccharide, RNA, mitochondrial DNA, histones
etc), cytokines, chemokines, bioactive lipid mediators,
recep-tors on both innate and adaptive immunity cells for the
above molecules, and reactive oxygen species
Epithelial cells, neutrophils, monocytes, macrophages,
dendritic cells, Natural Killer Cells, mast cells, T and B
lym-phocytes constitute the group of cells implicated in the
pro-cess [1]
* Address correspondence to this author at the Department of Medicine,
Faculty of Life Sciences, Democritus University of Thrace, 68100
Alexan-droupolis, Greece; Tel/Fax: ++30-25510-30502;
E-mail: kanagnos@med.duth.gr
Apart from the various types of cells mentioned above, emerging data highlight a potential immune-modulatory role
of erythro-cytes Indeed, within the context of evolutionary biology, non-mammalian vertebrate erythro-cytes have an important immunomodulatory function [2] However, in th-ese animals, erythrocytes are nucleated in contrast to human ones Nevertheless, human erythron-cytes retain a
consider-able immunomodulatory capacity [2, 3] (Fig 1).
The normal functioning of red blood cells requires the presence of certain micro- and macromolecules These molecules ensure the appropriate energy metabolism priori-ties, help to maintain the proper antioxidant capacity and af-fect normal cell death and clearance How-ever, under condi-tions of tissue injury, the release of some of these molecules, which normally are not available in the extracellular environ-ment, leads to their recognition as DAMP Others, induce oxidative stress
It also appears that red blood cells possess several macro-molecules, through which they can scavenge pro-inflamma-tory agents from the site of inflammation However, due to acquired or genetic differences in the red blood cells ability
to remove these factors, this function may be negligible to re-duce inflammation and / or increase it
2212-3873/21 $65.00+.00 © 2021 Bentham Science Publishers
Trang 2Fig (1) Immunomodulatory functions of human erythrocytes This figure was created using Servier Medical Art templates, which are
li-censed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.
Fig (2) Potential molecular mechanisms for the biosynthesis of signalling lipids in human erythrocytes This figure was created using
Servi-er Medical Art templates, which are licensed undServi-er a Creative Commons Attribution 3.0 Unported License; https://smart.sServi-erviServi-er.com.
Lipid signaling, through interfering with signaling
net-works, regulates a range of cellular functions, such as
metabolism, inflammation-related signaling, cell
prolifera-tion, growth, motility, apoptosis and autophagy [4] Thus,
lipids are implicated in the molecular basis of human
dis-ease, including those affecting metabolism, immune system,
nervous system, and cancer The cellular source of these
lipids includes an array of cells However, the role of
ery-throcytes is usually underestimated, leading to the possible
ignorance of many molecular therapeutic targets (Fig 2).
Erythrocytes comprise 45% of the total blood volume, while lipids make up 40% of the red blood cell mass [5] Fur-thermore, the concentration of cholesterol in erythrocytes is similar to that of lipoproteins [6] Red blood cells exchanges cholesterol and phospholipids with lipoproteins [7, 8] In ad-dition, erythrocytes have been shown to participate in
macrophages to the liver [9] Therefore, the erythrocyte has characteristics that make it an ideal lipid carrier in the blood
(Fig 3) However, contrary to lipoproteins, erythrocytes,
Trang 3Fig (3) Contribution of erythrocytes to reverse cholesterol transport This figure was created using Servier Medical Art templates, which are
licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.
despite the absence of intracellular organelles, can
metabol-ize membrane lipids, resulting in the formation of bioactive
lipids
In this review, we attempt to bring light to the possible
role of red blood cells in inflammation and
im-munometabolism, to reveal novel therapeutic targets
2 ERYTHROCYTES IN OXIDATIVE STRESS
Under normal conditions, the erythrocyte can function as
an antioxidant cellular agent as it passes through the tissues
This is due to its antioxidant properties: GSH, NADH and
NADPH and its antioxidant enzymes: peroxide dismutase,
catalase, peroxidase, glutathione peroxidase, peroxidizing 2
and glutaredoxin 2 [10] As the age of the erythrocyte
in-creases, so does the concentration of oxidized proteins
(Bar-tosz, 1981), but also the oxidation of hemoglobin [11]
Among the antioxidants of the erythrocytes (GSH, NADH
and NADPH), GSH plays a particularly important role,
since its biosynthesis [12] is the only way for its production
GSH production, however, decreases with increasing
ery-throcyte age due to reduced glucose entry [13], decreased
pyruvate kinase activity, dehydrogenase 6-phosphate
glu-cose, and aminotransferase aspartic
In addition, passing through tissue with oxidative stress
leads to converting the erythrocyte from an antioxidant to a
pro-oxidative cell [10]
Red blood cells with reduced antioxidant potential are
likely to be actively involved in inflammation The
interac-tion of oxidized erythrocytes with monocytes in the
pres-ence of LPS or zymosan, led to an increase in TNF-α and
IL-10 production [14] Aoshiba et al., showed that
ex-tracellular levels, which could diffuse into the cell and cause
neutrophil apoptosis However, the suppression of
erythro-cyte’s glutathione metabolism did not allow the protective
properties of erythrocyte versus neutrophil apoptosis [15] Fi-nally, erythrocytes’ antioxidant capacity is implicated in the inhibition of apoptosis and the cell death-associated oxida-tive stress of T lymphocytes; this requires intact erythro-cytes to come into contact with T lymphoerythro-cytes [16]
3 DAMP RELEASE 3.1 Heme and Hemoglobin Release
Hemoglobin, while inside the red blood cell, is protected from oxidation However, its release makes it prone to oxida-tion Oxidized hemoglobin triggers the formation of com-plexes that are sources of free radicals such as methemo-globin In fact, oxidation of hemoglobin can also be caused
by peroxidized lipids [17]
Heme and oxidized hemoglobin can lead to the induc-tion of expression of various adhesion molecules in endothe-lial cells such as ICAM1, VCAM1 and E-Selectin [18, 19]
In fact, oxidized hemoglobin has led to the re-organization
of cell cytoskeleton resulting in increased permeability of the endothelial gaps [19] In addition, a study has shown that heme causes chemotaxis in neutrophils [20] The effect of heme in inflammation seems to require TLR4 and NFKβ [21]
A study by Buttari et al., shows that heme causes
chemo-tactic activity in monocytes but also in dendritic cells de-rived from monocytes Endothelial cell attachment and en-dothelial migration have also been implicated This action appears to require the attachment of hemoglobin to CD163, signaling via ERK and MAPK, and cell cycle rearrange-ment In fact, the study suggests that oxidized hemoglobin may have the same effect since the administration of amino acetylcysteine reduced the incidence of chemotaxis [22]
Trang 43.2 ATP Release
Sikora et al., showed that erythrocytes release ATP after
hemolysis and that this release is not subject to regulation by
mechanical pressure, hypoxia or cAMP [23] The ATP
re-leased could have immunomodulatory effects ATP causes
chemotaxis in neutrophils, macrophages, and dendritic cells
[24], regulates the function of T lymphocytes depending on
its concentration [25] and affects the concentrations of IL-1β
cytokines, TNF-α and IL-10 [26]
3.3 Vesicle Release
As erythrocytes age, vesicles are produced, which
ap-pear to require or at least be associated with the hydrolysis
of phosphoinositides to diacylglycerol, but also the
external-ization of PSer In addition, the hydrolysis of SM by the
acidic sphingomyelinase of the erythrocyte can lead to the
production of microparticles [27]
Sadallah et al [28] found that erythrocytes release
vesi-cles which, due to their size, the presence of lipid membrane
and specific proteins, can be characterized as ectosomes In
fact, these ectosomes expressed PSer on their surface and
were phagocytosed by macrophages and led to a reduced
ex-pression of TNF-α and CXCL8 (IL-8) by macrophages
stim-ulated by LPS or Zymozan A Therefore, it appears that
th-ese ectosomes have immunosuppressive properties
Microparticles released by erythrocytes attach to
mono-cytes, triggering the release of pro-inflammatory cytokines,
resulting in the proliferation of CD4 + and CD8 + T
lympho-cytes [29] A study by Belizaire et al [30] found that
micro-particles released by stored red blood cells activate
neu-trophils as shown by CD11b expression, oxidative stress and
phagocytic capacity
3.4 Cytokine Release
IL-33 is a cytokine, mainly located in the nucleus Its
re-lease can function as a DAMP In addition, IL-33 possess
pleiotropic immune function, since it can regulate the
devel-opment and/or function of Innate Lymphoid Cells 2, T
T
lymphocytes and Natural Killer Cells [31] Wei et al [32],
showed that IL-33 is expressed in erythroid cells and is
re-leased by the mature erythrocyte through hemolysis; in fact
IL-33 levels are released by erythrocytes significantly affect
and relate to cytokine levels blood The same investigators
also reported that IL-33 could induce the expression of IL 8
in airway epithelial cells
Evidently, the release of cytokines from erythrocytes has
been validated ex vivo Karsten et al., showed that
erythro-cytes of healthy volunteers could release, during culture in
PBS, more than 40 cytokines and chemokines; the same
study showed that erythrocytes, when incubated with
recom-binant cyto-kines and chemokines, reduce their content in
the conditioned medium [33]
AGENTS 4.1 Duffy Blood Group and Chemokine Scavenging
Darbonne et al [34], were the first to show that
erythro-cytes, through the Duffy Blood group antigen, bind the chemokines CXCL8 (IL-8) and CCL2 (MCP1) In fact, the same study showed that the binding of chemokines to the erythrocyte receptor did not cause its internalization, while the chemokines that remained bound to the receptor did not exert their action on other cells Subsequent studies show that this receptor binds, in addition to CXCL8 and CCL2 and CCL5 (RANTES), MGSA, NAP-2 and others [35]
However, Yamamoto et al [36], argue that DARC together
with bound cytokines can be internalized and therefore re-tain cytokines
Of particular importance is the fact that the loss of DARC from erythrocytes leads to inflammation of the lungs [37] In addition, binding of chemokines CXCL1 and CX-CL2/3 to DARC has been found to protect against neu-trophil migration and airway inflammation [38] In fact, it ap-pears that the expression of DARC in non-hematopoietic cells does not affect the above events, thus demonstrating the role of this receptor in the red blood cell [38] Erythro-cytes, possibly through the Duffy blood group and the bind-ing of CCL5/RANTES, affect the endothelial migration of eosinophils, which is particularly important in inflammation during allergy [39] Finally, it is possible that despite the par-ticipation of DARC in scavenging chemokine in circulation,
it could at the same time increase their half-life
4.2 Erythropoietin Receptor and IL-2 Scavenging
Kirtch et al [40], showed that incubation of IL-2 with
erythrocytes leads to the binding of a considerable number
of IL-2 molecules to the erythropoietin receptor expressed in immature and new erythrocytes, even after multiple washes
In fact, it appears that this is due to the similarity between the erythropoietin receptor and the IL-2 receptor In addi-tion, reticulocytes bind 400% more IL-2 than mature cytes [41] Subsequently, another study showed that erythro-cytes could be used as carriers of IL-2, which could release and enhance cytotoxicity [42]
4.3 TLR9 and Mitochondrial DNA Scavenging
TLR9 is a member of the toll-like receptor family, and is expressed mainly by innate immunity cells Its function is in recognition of bacterial, viral and mitochondrial DNA [43]
Hotz et al [44], showed that erythrocytes express TLR9
and under normal conditions impart a significant amount of mitochondrial DNA However, in the case of systemic in-flammation, most mtDNA is not associated with red blood cell TLR9 In fact, the lack of TLR9 from erythrocytes led
to inflammation in vivo The same study revealed important
inter- and intra-individual variation regarding erythrocyte TLR9 levels
Trang 5As in the case of DARC, TLR9 could increase the
half-life of cell-free mitochondrial DNA, releasing it when or
where the concentration of cell-free mitochondrial DNA is
low [2]
4.4 Complement Receptor 1 and Complement
Scaven-ging
The erythrocytes possess the complement receptor 1
(CR1) which binds immune complexes that have attached
the protein to the C3b supplement and then the erythrocyte
carries these immune complexes to remove liver phagocytes
[45] The CR1 genotype is likely to affect C3b binding
ca-pacity [46] Acquired CR1 reductions include release
through ectosomes, but mainly through proteolysis that is
likely to be induced in the in vivo disease environment [45].
5 IMMUNE REGULATION THROUGH PHYSICAL
INTERACTION
5.1 CD47
CD47 plays an important role in the removal of
erythro-cytes CD47 is recognized by the SIPR receptor and acts as
a self-marker and as a “do not eat me” signal to the
phago-cytes that express the receptor [47] However, Burger et al.
[48], showed that in vitro-aging red blood cells underwent a
change in CD47 steroid formation, thereby binding to
TSP-1 Also, peptide administration of TSP-1 led to
ery-throphagocytosis The change in CD47 structure and its
asso-ciation with TSP-1 was also observed in red blood cells that
had been stored for a long time These results led the
re-searchers in the above study to classify CD47 as a
“molecu-lar switch”
Schakel et al., showed that erythrocytes, through the
in-teraction of CD47 with SIPR, prevent the maturation of a
subtype of dendritic cells characterized by the modification
of 6-sulfo LacNac of PSGL-1 and differentiate from
leuko-cytes In addition, the same study showed that erythrocytes
prevented the release of IL-12 and TNF-α [49]
Subsequently, Buttari et al [50], showed again that
ery-throcytes from healthy people prevent the maturation of
den-dritic cells exposed to LPS and this was accompanied by
re-duced amounts of IL-12, IL-6, TNF-α and increased
amounts of IL-10 What is remarkable about this study,
how-ever, is that erythrocytes from patients with arteriosclerosis
did not prevent the maturation of dendritic cells from
healthy controls This was accompanied by an increase in
the amount of IL-6, IL-12, TNF-α and reduced amounts of
IL-10 The erythrocytes of these patients showed increased
oxidative stress, reduced amounts of glycophorin A, CD47
and increased PSer on the extracellular side of the lipid
bilay-er of bilay-erythrocytes The above data led the authors to assume
that the reduced amount of CD47 in erythrocytes causes the
inability of erythrocytes to inhibit the maturation of
dendrit-ic cells
5.2 Glycophorin A
Erythrocytes suppress the activation of neutrophils
through the binding of glycophorin A to Siglec-9 of
neu-trophils, as shown by oxidative stress, chemotaxis, produc-tion of extracellular traps, apoptosis, etc Inhibiproduc-tion of this in-teraction is associated with neutrophil activation [51] De-creased glycophorin A has been found in aged red blood cells [52], indicating that aging of red blood cells reduces an-tioxidant capacity, lowering glycophorin A and increasing production of microvesicles, leads to the activation of neu-trophils
5.3 Externalisation of Phosphatidylserine
The externalization of PSer in erythrocytes has been found to be a feature of the aging of these cells In a study
by Boas et al [53], the externalization of PSer was found to
be increased in aged erythrocytes and was associated with the removal of these erythrocytes from circulation
Howev-er, Franco et al., observed, after re-administration of
erythro-cytes, that the externalization of PSer was not observed in aged erythrocytes [54] What is likely to be the case is that the externalization of PSer occurs more easily in aged ery-throcytes after eryptosis (erythrocyte apoptosis) induction [13] However, inflammation can cause the externalization
of PSer by increasing the number of sphingomyelinases in the blood that could subsequently act on the erythrocyte [55] Furthermore, cholesterol loading in the erythrocyte membrane inhibits the externalization of PSer [56] In any case, externalized phosphatidylserine can be recognized by macrophage receptors as well as Tim-1, Tim-4 and Stabilin-i-2 In addition, lactaderin, GAS6, and protein S act as a
AXL family receptors [57]
A study shows that both in vitro and in vivo
accumula-tion of erythrocytes in the liver occurs during hepatic steato-sis These erythrocytes, due to oxidative stress externalize the PSer, which is recognized by the Kupffer cells and then erythrophagocytosis occurs This has been linked to in-creased hepatic oxidative stress and inflammation [58]
6 LIPID SIGNALING 6.1 S1P Release
S1P is bioactive lysophospholipid It creates a gradient
in blood; a mechanism necessary for lymphocyte egression from lymphoid organs In addition S1P contributes to
inflam-mation and vascular development [59] Hanel et al [60]
found that erythrocytes constitute a particularly important source of plasma S1P, mainly through their plasma mem-brane In fact, erythrocytes contain 54% of total S1P in blood In each case, erythrocytes determine S1P levels in the blood, as transfusion of erythrocytes into experimental ani-mals lacking sphingosine kinase 1/2 restored S1P plasma lev-els [61]
Hanel et al also showed that erythrocytes do not
synthe-size S1P, since an inverse relationship was observed be-tween the levels of this lipid metabolite in plasma and ery-throcyte Finally, a dynamic equilibrium between the two
compartments was observed in vivo [60].
However, in the erythrocyte, there is an active form of acid sphingomyelinase - an enzyme that hydrolyzes
Trang 6sphin-gomyelin to produce ceramide This enzyme is increased
un-der hypoxia in erythrocytes of sickle cell anemia [27] In
ad-dition, erythrocytes contain ceramidase - an enzyme that
cleaves ceramide to sphingosine Inhibition of this enzyme
decreased the levels of sphingosine and S1P in erythrocytes
[62] It is particularly important that erythrocytes also
con-tain active sphingosine kinase In fact, its activity increases
during periods of hypoxia through adenosine binding to the
A2B receptor in the red blood cell, leading to ERK1 / 2
sig-naling The end result is an increase in S1P levels [63]
Fur-thermore, the red blood cell can respond to low plasma S1P
levels by increasing the activity of sphingosine kinase 1
[64]
Subsequently, studies by Bode et al [65], found that the
red cell releases S1P to high-density lipoproteins and plasma
albumin In fact, HDLs carry greater amounts of S1P than
al-bumin A study by Christensen et al [66] showed that the
majority of HDL- bound S1P molecules are associated with
apolipoprotein M (apoM) This was observed even in the
absence of the remaining molecules of the HDL complex
Fi-nally, the exchange of S1P from erythrocytes to apoM was
found to be sensitive to inhibition of ABCC1 but not of
ABCB1 In contrast to the above study, Vu et al [67]
showed that the Mfsd2b transporter is particularly important
for the release of S1P from erythrocytes and platelets
Final-ly, another study showed that Band 3 also participates in the
release of S1P from erythrocytes [68] Regardless of the
car-rier responsible for the transport of S1P from the erythrocyte
to plasma / serum, it appears to be S1P-specific, as lipids
with similar structure did not inhibit S1P transport [69]
6.2 LPC and LPA Release
LPA.is another bioactive lysophospholipid that acts
through the activation of five receptors Its role in
inflamma-tion is well recognized [70] Cripps et al [71], have shown
that erythrocytes contain lysophosphatidic acid
acyltrans-ferase (LPAAT) enzyme in their membrane, which converts
plasma LPA to phosphatidic acid (PA) In fact, it was found
that the red blood cell regulates serum LPA levels In
addi-tion, Phosphatidic acid in erythrocytes with PSer
external-ized appears to be hydrolyzed by phospholipase A2, an
en-zyme which increases during inflammation, and results in
in-creased LPA in erythrocytes [72] Subsequently, Cripps et
al showed that erythrocyte storage reduces the activity of
the LPA acetyltransferase enzyme, thereby increasing the
amount of LPA in the red blood cell [73], which can then
ex-ert its pharmacological actions
Alternatively, the red blood cells may release a substrate
for lysophospholipase D, LPC, which can further be
convert-ed to LPA This is at least indicative of a study by Aoki et
al.; LPC was found in the erythrocyte incubation
superna-tant and the addition of exogenous lysophospholipase D
in-creased LPA levels [74] Erythrocytes also contain the
en-zyme cytosolic phospholipase A2 [75] In fact, its levels
in-crease under hypoxia via ERK signaling and regulate LPC
levels in the red blood cell [76]
6.3 LTB4 Release
The red blood cells appear to possess the ability to synth-esize some eicosanoids In particular, red blood cells can me-tabolize leukotriene LTA4 to LTB4 as they contain the en-zyme LTA4 hydrolase [77]
6.4 PGE1 and PGE2 Synthesis
In addition, red blood cells can also synthesize prostag-landins PGE1 and PGE2 [78] The metabolic pathway has not been extensively studied, but cyclooxygenase 1 (COX-1), which acts in the initial steps of synthesizing these bioactive lipids, has been found [78]
6.5 PAF Release
According to Lang et al., the erythrocyte, in response to
the hyperosmotic shock, synthesizes PAF, which is released
by the cell, acts in autocrine signaling, and activates its re-ceptor in the erythrocyte surface, causing sphingomyelinase activation and ceramide production This pathway is
possib-ly involved in eryptosis [79] Whether this circuit has paracrine action merits further examination
6.6 EET Release
EET is anti-inflammatory bioactive lipids, whose metabolism has been explored as potential therapeutic tar-gets [80] Erythrocytes can synthesize and release EET after specific stimuli It has been found that the stimulation of the P2X7 receptor by ATP promotes the release of EETs [81] The pathway probably starts with the release of AAs from the erythrocyte membrane phospholipids after phospholi-pase activity [82] The action of the hemoglobin monooxyge-nase follows by the aid of nicotinic acid or riboflavin [83] Indeed, the release of EETs from erythrocytes determines plasma EET levels [84] Finally, the erythrocyte contains an active epoxide hydrolase enzyme that hydrolyzes the EETs Inhibition of this enzyme increases plasma EETs levels [85]
6.7 12(S)-HETE Release
A study by Kobayashi and Levine [86] showed that ery-throcytes, after an increase in intracellular calcium concen-tration, induced the production of 12(S)-HETE, which is im-munologically active The source of arachidonate was PC and PE, indicating that phospholipase A2 is involved in AA mobilization and not phospholipase C Then, the activity of lipoxygenase is followed [87] 12(S)-HETE was found in the erythrocyte supernatant, indicating that red cells release these bioactive lipids [86]
7 CONTRIBUTION TO REVERSE CHOLESTEROL TRANSPORT
Erythrocytes make up 45% of total blood volume, while lipids comprise 40% of red blood cell mass Also, the con-centration of cholesterol in erythrocytes is similar to that of lipoproteins [6]
In humans, erythrocytes exchange phospholipids and cholesterol with lipoproteins (7, 8 Kinetic studies show that
Trang 7cholesterol moves between red blood cells and lipoproteins
via aqueous diffusion [7].
About 50% of blood cholesterol is found in erythrocytes,
indicating that the flow of cholesterol to the erythrocyte is
similar to the efflux of free cholesterol from the tissues [88]
A study found that in mice lacking the apoAI gene, the
reverse transport of cholesterol occurs to a large extent from
the red blood cell In mice that did not lack apoAI, the
ery-throcyte was found to be involved, but to a lesser extent
The model suggested by the authors is that red blood cells
re-ceive cholesterol from LDL and HDL and transfer it either
directly to the liver cells or to the endothelial cells [9]
However, the transfer of cholesterol from red blood cells
to the liver could be done through very-low-density
lipopro-teins/chylomicrons A study by Chung et al [89], found
that incubating erythrocytes with autologous plasma after
fasting containing LCAT and CETP proteins for 18 hours at
37 degrees led to an increase in plasma cholesterol through a
concomitant increase in esterified cholesterol of HDL, LDL
and VLDL The postprandial plasma containing
chylomi-crons led to a greater rise in plasma cholesterol, leading to a
356% elevation of cholesterol levels in chylomicrons The
ability of plasma to receive cholesterol from red blood cells
was positively correlated with plasma cholesterol,
triglyc-erides, VLDL, LDL These results were confirmed in a
sub-sequent study [90] Therefore, chylomicrons accept free
cholesterol from red blood cells and can then transport it to
the liver through their remnants In the above mechanism,
apolipoprotein B, which is associated with erythrocytes,
may be involved The amount of apoB in red blood cells is
not related to serum apoB levels [91]
Others showed that erythrocytes contribute to reverse
cholesterol transport by providing PC regeneration from
LCAT-formed LPC [92] Finally, a recent study showed that
red blood cells indirectly accept cholesterol from
macrophages The same study also showed that erythrocytes
possibly donate cholesterol to albumin and apoA1, but do
not accept cholesterol from apoA1 [93] These data imply
that the erythrocyte constitutes an important mediator of
cholesterol transport in the circulation
CONCLUSION
It is now evident that erythrocytes not only contribute to
innate immunity regulation, but they are also capable of
de-termining important components of adaptive immunity
Nev-ertheless, erythrocyte immunobiology remains elusive
Vari-ous receptors implicated in the binding of inflammatory
agents are found in erythrocyte membranes However, a lot
of questions merit investigation: kinetics, interactions,
mech-anisms of surface-level reductions Furthermore, the
crosstalk between aging, induction of eryptosis and release
of DAMPs contains a lot of unknowns
The molecular mechanisms for the function of
erythro-cyte-derived lipid mediators remain unexplored Despite the
progress regarding the understanding of lipid biology, many
questions need to be addressed Which transporters permit
the release of the lipid mediators by the erythrocytes? Which signaling pathways regulate the activity of the enzymes re-sponsible for the biosynthesis of these lipids? Is the release
of these lipid mediators affected during immune-metabolic and neurometabolic diseases such as non-alcoholic fatty
liv-er disease, athliv-erosclliv-erosis and Alzheimliv-er’s disease? Is the synthesis and release of these lipids a group of therapeutic targets?
Finally, red blood cells constitute a neglected “lipopro-tein” capable of influencing cholesterol trafficking in tis-sues Exploration of the implicated mechanisms shall unveil novel therapeutic targets
It is our opinion that the answers to these questions could plausibly reveal cellular and a handful of molecular novel therapeutic targets
LIST OF ABBREVIATIONS
ADORA2B = Adenosine A2B Receptor
2b
Trang 8NADPH = Nicotinamide Adenine Dinucleotide
Phos-phate
of activated B cells
CONSENT FOR PUBLICATION
Not applicable
FUNDING
The research work was supported by the Hellenic
Foun-dation for Research and Innovation (HFRI) under the HFRI
Ph.D Fellowship grant (Fellowship Number: 1343)
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise
ACKNOWLEDGEMENTS
Declared none
REFERENCES
Chen, L.; Deng, H.; Cui, H.; Fang, J.; Zuo, Z.; Deng, J
Inflamma-[1]
tory responses and inflammation-associated diseases in organs.
Vol 9 Oncotarget Impact Journals, 2018, LLC, 7204-7218.
http://dx.doi.org/10.18632/oncotarget.23208
Anderson, H.L.; Brodsky, I.E.; Mangalmurti, N.S The Evolving
[2]
Erythrocyte: Red Blood Cells as Modulators of Innate Immunity.
J Immunol., 2018, 201(5), 1343-1351.
http://dx.doi.org/10.4049/jimmunol.1800565 PMID: 30127064
Buttari, B.; Profumo, E.; Riganò, R Crosstalk between red blood
[3]
cells and the immune system and its impact on atherosclerosis.
BioMed Res Int., 2015, 2015616834
http://dx.doi.org/10.1155/2015/616834 PMID: 25722984
Barnett, K.C.; Kagan, J.C Lipids that directly regulate innate
im-[4]
mune signal transduction Innate Immun., 2020, 26(1), 4-14.
http://dx.doi.org/10.1177/1753425919852695 PMID: 31180799
Dodge, J.T.; Mitchell, C.; Hanahan, D.J The preparation and
[5]
chemical characteristics of hemoglobin-free ghosts of human
ery-throcytes Arch Biochem Biophys., 1963, 100(1), 119-130.
http://dx.doi.org/10.1016/0003-9861(63)90042-0 PMID: 14028302
Nikolić, M.; Stanić, D.; Antonijević, N.; Niketić, V Cholesterol [6]
bound to hemoglobin in normal human erythrocytes: a new form
of cholesterol in circulation? Clin Biochem., 2004, 37(1), 22-26.
http://dx.doi.org/10.1016/j.clinbiochem.2003.10.002 PMID: 14675558
Dmitry, Y Lipids that directly regulate innate immune signal [7]
transduction Innate Immunity , 2018, 26 (1 ), 4 -14
Dushianthan, A; Cusack, R; Koster , G.; Grocott, M.; Postle, A In-[8]
sight into erythrocyte phospholipid molecular flux in healthy hu-mans and in patients with acute respiratory distress syndrome
PLOS ONE, 2019, 14(8), 02215959.
http://dx.doi.org/10.1161/ATVBAHA.112.248971 PMID: 22499994
Hung, KT; Berisha, SZ; Ritchey, BM; Santore, J; Smith, JD Red [9]
Blood Cells Play a Role in Reverse Cholesterol Transport
Arterios-cler Thromb Vasc Biol., 2012, 32(6), 1460-5.
Minetti, M.; Agati, L.; Malorni, W The microenvironment can [10]
shift erythrocytes from a friendly to a harmful behavior:
pathoge-netic implications for vascular diseases Cardiovasc Res., 2007,
75(1), 21-28.
http://dx.doi.org/10.1016/j.cardiores.2007.03.007 PMID: 17412313
Rifkind, J.M.; Nagababu, E Hemoglobin redox reactions and red [11]
blood cell aging Antioxid Redox Signal., 2013, 18(17),
2274-2283.
http://dx.doi.org/10.1089/ars.2012.4867 PMID: 23025272 Lutz, H.U.; Bogdanova, A Mechanisms tagging senescent red [12]
blood cells for clearance in healthy humans Front Physiol., 2013,
4, 387.
http://dx.doi.org/10.3389/fphys.2013.00387 PMID: 24399969 Ghashghaeinia, M.; Cluitmans, J.C.A.; Akel, A.; Dreischer, P.; [13]
Toulany, M.; Köberle, M.; Skabytska, Y.; Saki, M.; Biedermann, T.; Duszenko, M.; Lang, F.; Wieder, T.; Bosman, G.J The impact
of erythrocyte age on eryptosis Br J Haematol., 2012, 157(5),
606-614.
http://dx.doi.org/10.1111/j.1365-2141.2012.09100.x PMID: 22429222
Liese, A.M.; Siddiqi, M.Q.; Siegel, J.H.; Denny, T.; Spolarics, Z [14]
Augmented TNF-alpha and IL-10 production by primed human monocytes following interaction with oxidatively modified
autolo-gous erythrocytes J Leukoc Biol., 2001, 70(2), 289-296.
PMID: 11493622 Aoshiba, K.; Nakajima, Y.; Yasui, S.; Tamaoki, J.; Nagai, A Red [15]
blood cells inhibit apoptosis of human neutrophils Blood, 1999,
93(11), 4006-4010.
http://dx.doi.org/10.1182/blood.V93.11.4006 PMID: 10339510 Fonseca, A.M.; Porto, G.; Uchida, K.; Arosa, F.A Red blood cells [16]
inhibit activation-induced cell death and oxidative stress in human
peripheral blood T lymphocytes Blood, 2001, 97(10), 3152-3160.
http://dx.doi.org/10.1182/blood.V97.10.3152 PMID: 11342443 Jeney, V.; Balla, G.; Balla, J Red blood cell, hemoglobin and [17]
heme in the progression of atherosclerosis Front Physiol., 2014,
5, 379.
http://dx.doi.org/10.3389/fphys.2014.00379 PMID: 25324785 Wagener, F.A.D.T.G.; Feldman, E.; de Witte, T.; Abraham, N.G [18]
Heme induces the expression of adhesion molecules ICAM-1,
VCAM-1, and E selectin in vascular endothelial cells Proc Soc.
Exp Biol Med., 1997, 216(3), 456-463.
http://dx.doi.org/10.3181/00379727-216-44197 PMID: 9402154 Silva, G.; Jeney, V.; Chora, A.; Larsen, R.; Balla, J.; Soares, M.P [19]
Oxidized hemoglobin is an endogenous proinflammatory agonist
that targets vascular endothelial cells J Biol Chem., 2009,
284(43), 29582-29595.
http://dx.doi.org/10.1074/jbc.M109.045344 PMID: 19700768 Monteiro, A.P.; Pinheiro, C.S.; Luna-Gomes, T.; Alves, L.R.; [20]
Maya-Monteiro, C.M.; Porto, B.N.; Barja-Fidalgo, C.; Benjamim, C.F.; Peters-Golden, M.; Bandeira-Melo, C.; Bozza, M.T.;
Canet-ti, C Leukotriene B4 mediates neutrophil migration induced by
heme J Immunol., 2011, 186(11), 6562-6567.
http://dx.doi.org/10.4049/jimmunol.1002400 PMID: 21536805
Trang 9Belcher, J.D.; Chen, C.; Nguyen, J.; Milbauer, L.; Abdulla, F.;
[21]
Alayash, A.I.; Smith, A.; Nath, K.A.; Hebbel, R.P.; Vercellotti,
G.M Heme triggers TLR4 signaling leading to endothelial cell
ac-tivation and vaso-occlusion in murine sickle cell disease Blood,
2014, 123(3), 377-390.
http://dx.doi.org/10.1182/blood-2013-04-495887 PMID:
24277079
Buttari, B.; Profumo, E.; Di Cristofano, C.; Pietraforte, D.;
Lionet-[22]
ti, V.; Capoano, R.; Salvati, B.; Businaro, R.; Di Giammarco, G.;
Riganò, R Haemoglobin triggers chemotaxis of human
mono-cyte-derived dendritic cells: possible role in atherosclerotic lesion
instability Atherosclerosis, 2011, 215(2), 316-322.
http://dx.doi.org/10.1016/j.atherosclerosis.2010.12.032 PMID:
21333994
Sikora, J.; Orlov, S.N.; Furuya, K.; Grygorczyk, R Hemolysis is a
[23]
primary ATP-release mechanism in human erythrocytes Blood,
2014, 124(13), 2150-2157.
http://dx.doi.org/10.1182/blood-2014-05-572024 PMID:
25097178
Sáez, P.J.; Vargas, P.; Shoji, K.F.; Harcha, P.A.;
Lennon [24]
Duménil, A-M.; Sáez, J.C ATP promotes the fast migration of
dendritic cells through the activity of pannexin 1 channels and
P2X 7 receptors Sci Signal., 2017, 10(506)eaah7107
http://dx.doi.org/10.1126/scisignal.aah7107 PMID: 29162744
Trabanelli, S.; Ocadlíková, D.; Gulinelli, S.; Curti, A.; Salvestrini,
[25]
V.; Vieira, R.P.; Idzko, M.; Di Virgilio, F.; Ferrari, D.; Lemoli,
R.M Extracellular ATP exerts opposite effects on activated and
regulatory CD4+ T cells via purinergic P2 receptor activation J.
Immunol., 2012, 189(3), 1303-1310.
http://dx.doi.org/10.4049/jimmunol.1103800 PMID: 22753942
Cauwels, A.; Rogge, E.; Vandendriessche, B.; Shiva, S.;
Brouck-[26]
aert, P Extracellular ATP drives systemic inflammation, tissue
da-mage and mortality Cell Death Dis., 2014, 5(3), e1102-e1102.
http://dx.doi.org/10.1038/cddis.2014.70 PMID: 24603330
Awojoodu, A.O.; Keegan, P.M.; Lane, A.R.; Zhang, Y.; Lynch,
[27]
K.R.; Platt, M.O.; Botchwey, E.A Acid sphingomyelinase is
acti-vated in sickle cell erythrocytes and contributes to inflammatory
microparticle generation in SCD Blood, 2014, 124(12),
1941-1950.
http://dx.doi.org/10.1182/blood-2014-01-543652 PMID:
25075126
Sadallah, S.; Eken, C.; Schifferli, J.A Erythrocyte-derived
ecto-[28]
somes have immunosuppressive properties J Leukoc Biol., 2008,
84(5), 1316-1325.
http://dx.doi.org/10.1189/jlb.0108013 PMID: 18685086
Danesh, A.; Inglis, H.C.; Jackman, R.P.; Wu, S.; Deng, X.;
[29]
Muench, M.O.; Heitman, J.W.; Norris, P.J Exosomes from red
blood cell units bind to monocytes and induce proinflammatory
cy-tokines, boosting T-cell responses in vitro Blood, 2014, 123(5),
687-696.
http://dx.doi.org/10.1182/blood-2013-10-530469 PMID:
24335232
Belizaire, R.M.; Prakash, P.S.; Richter, J.R.; Robinson, B.R.;
Ed-[30]
wards, M.J.; Caldwell, C.C.; Lentsch, A.B.; Pritts, T.A
Micropar-ticles from stored red blood cells activate neutrophils and cause
lung injury after hemorrhage and resuscitation J Am Coll Surg.,
2012, 214(4), 648-655.
http://dx.doi.org/10.1016/j.jamcollsurg.2011.12.032 PMID:
22342784
Liew, F.Y.; Girard, J.P.; Turnquist, H.R Interleukin-33 in health
[31]
and disease.Nature Reviews Immunology; Nature Publishing
Group, 2016, 16, pp 676-689.
Wei, J.; Zhao, J.; Schrott, V.; Zhang, Y.; Gladwin, M.; Bullock,
[32]
G.; Zhao, Y Red Blood Cells Store and Release Interleukin-33 J.
Investig Med., 2015, 63(6), 806-810.
http://dx.doi.org/10.1097/JIM.0000000000000213 PMID:
26107423
Karsten, E.; Breen, E.; Herbert, B.R Red blood cells are dynamic
[33]
reservoirs of cytokines Sci Rep., 2018, 8(1), 3101.
http://dx.doi.org/10.1038/s41598-018-21387-w PMID: 29449599
Darbonne, W.C.; Rice, G.C.; Mohler, M.A.; Apple, T.; Hébert,
[34]
C.A.; Valente, A.J.; Baker, J.B Red blood cells are a sink for
inter-leukin 8, a leukocyte chemotaxin J Clin Invest., 1991, 88(4),
1362-1369.
http://dx.doi.org/10.1172/JCI115442 PMID: 1918386 Hansell, CA; Hurson, CE; Nibbs, RJ DARC and D6: silent partn-[35]
ers in chemokine regulation? Immunol Cell Biol., 2011, 89(2),
197-206.
http://dx.doi.org/10.7754/Clin.Lab.2016.161027 PMID: 28397469 Yamamoto, A.; Saito, N.; Ogasawara, S.; Shiratori, T.; Kondo, J.; [36]
Itoga, M Intracellular Storage of Duffy Antigen-Binding
Chemokines by Duffy-Positive Red Blood Cells Clin Lab, 2017,
63(4), 717-23.
Mangalmurti, N.S.; Xiong, Z.; Hulver, M.; Ranganathan, M.; Liu, [37]
X.H.; Oriss, T.; Fitzpatrick, M.; Rubin, M.; Triulzi, D.; Choi, A.; Lee, J.S Loss of red cell chemokine scavenging promotes
transfu-sion-related lung inflammation Blood, 2009, 113(5), 1158-1166.
http://dx.doi.org/10.1182/blood-2008-07-166264 PMID: 19064726
Reutershan, J.; Harry, B.; Chang, D.; Bagby, G.J.; Ley, K DARC [38]
on RBC limits lung injury by balancing compartmental
distribu-tion of CXC chemokines Eur J Immunol., 2009, 39(6),
1597-1607.
http://dx.doi.org/10.1002/eji.200839089 PMID: 19499525 Kanda, A.; Adachi, T.; Kayaba, H.; Yamada, Y.; Ueki, S.; Yam-[39]
aguchi, K.; Hamada, K.; Fujita, M.; Chihara, J Red blood cells regulate eosinophil chemotaxis by scavenging RANTES secreted
from endothelial cells Clin Exp Allergy, 2004, 34(10),
1621-1626.
http://dx.doi.org/10.1111/j.1365-2222.2004.02073.x PMID: 15479279
Kirch, H.J.; Moyes, R.B.; Chiarantini, L.; DeLoach, J.R Effect of [40]
targeted erythrocytes coated with recombinant human interleukin
2 on T-lymphocyte proliferation in vitro Biotechnol Appl.
Biochem., 1994, 19(3), 331-340.
PMID: 8031507 Moyes, R.B.; DeLoach, J.R Binding of human recombinant inter-[41]
leukin 2 to murine erythrocytes is erythropoietin receptor
mediat-ed Comp Haematol Int., 1996, 6(3), 134-140.
http://dx.doi.org/10.1007/BF00368456 Moyes, R.B.; Kirch, H.; DeLoach, J.R Enhanced biological activi-[42]
ty of human recombinant interleukin 2 coupled to mouse red blood cells as evaluated using the mouse Meth A sarcoma model.
Biotechnol Appl Biochem., 1996, 23(1), 29-36.
PMID: 8867894
Wagner, H The immunobiology of the TLR9 subfamily Trends in
[43]
Immunology , 2004, 25 , 381 -6
Hotz, M.J.; Qing, D.; Shashaty, M.G.S.; Zhang, P.; Faust, H.; [44]
Sondheimer, N.; Rivella, S.; Worthen, G.S.; Mangalmurti, N.S Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung
In-jury Am J Respir Crit Care Med., 2018, 197(4), 470-480.
http://dx.doi.org/10.1164/rccm.201706-1161OC PMID: 29053005 Pascual, M; Schifferli, JA Erythrocyte CR1 receptor: binding and [45]
transport of immune complexes in the blood circulation Schweiz
Med Wochenschr , 1993, 123 (3 ), 39 -43
Miyaike, J.; Iwasaki, Y.; Takahashi, A.; Shimomura, H.; [46]
Taniguchi, H.; Koide, N.; Matsuura, K.; Ogura, T.; Tobe, K.;
Tsu-ji, T Regulation of circulating immune complexes by complement
receptor type 1 on erythrocytes in chronic viral liver diseases Gut,
2002, 51(4), 591-596.
http://dx.doi.org/10.1136/gut.51.4.591 PMID: 12235086 Oldenborg, P-A CD47: A Cell Surface Glycoprotein Which Regu-[47]
lates Multiple Functions of Hematopoietic Cells in Health and
Dis-ease ISRN Hematol., 2013, 2013614619
http://dx.doi.org/10.1155/2013/614619 PMID: 23401787 Burger, P.; Hilarius-Stokman, P.; de Korte, D.; van den Berg, [48]
T.K.; van Bruggen, R CD47 functions as a molecular switch for
erythrocyte phagocytosis Blood, 2012, 119(23), 5512-5521.
http://dx.doi.org/10.1182/blood-2011-10-386805 PMID: 22427202
Schäkel, K.; von Kietzell, M.; Hänsel, A.; Ebling, A.; Schulze, L.; [49]
Haase, M.; Semmler, C.; Sarfati, M.; Barclay, A.N.; Randolph, G.J.; Meurer, M.; Rieber, E.P Human 6-sulfo LacNAc-expressing dendritic cells are principal producers of early interleukin-12 and
are controlled by erythrocytes Immunity, 2006, 24(6), 767-777.
Trang 10http://dx.doi.org/10.1016/j.immuni.2006.03.020 PMID: 16782032
Buttari, B.; Profumo, E.; Cuccu, B.; Straface, E.; Gambardella, L.;
[50]
Malorni, W.; Genuini, I.; Capoano, R.; Salvati, B.; Riganò, R
Ery-throcytes from patients with carotid atherosclerosis fail to control
dendritic cell maturation Int J Cardiol., 2012, 155(3), 484-486.
http://dx.doi.org/10.1016/j.ijcard.2011.12.068 PMID: 22265585
Lizcano, A.; Secundino, I.; Döhrmann, S.; Corriden, R.; Rohena,
[51]
C.; Diaz, S.; Ghosh, P.; Deng, L.; Nizet, V.; Varki, A Erythrocyte
sialoglycoproteins engage Siglec-9 on neutrophils to suppress
acti-vation Blood, 2017, 129(23), 3100-3110.
http://dx.doi.org/10.1182/blood-2016-11-751636 PMID:
28416510
Lutz, H.U.; Fehr, J Total sialic acid content of glycophorins
dur-[52]
ing senescence of human red blood cells J Biol Chem., 1979,
254(22), 11177-11180.
PMID: 500635
Boas, F.E.; Forman, L.; Beutler, E Phosphatidylserine exposure
[53]
and red cell viability in red cell aging and in hemolytic anemia.
Proc Natl Acad Sci USA, 1998, 95(6), 3077-3081.
http://dx.doi.org/10.1073/pnas.95.6.3077 PMID: 9501218
Franco, R.S.; Puchulu-Campanella, M.E.; Barber, L.A.; Palascak,
[54]
M.B.; Joiner, C.H.; Low, P.S.; Cohen, R.M Changes in the
proper-ties of normal human red blood cells during in vivo aging Am J.
Hematol., 2013, 88(1), 44-51.
http://dx.doi.org/10.1002/ajh.23344 PMID: 23115087
Dinkla, S.; Wessels, K.; Verdurmen, W.P.R.; Tomelleri, C.;
Cluit-[55]
mans, J.C.A.; Fransen, J.; Fuchs, B.; Schiller, J.; Joosten, I.;
Brock, R.; Bosman, G.J Functional consequences of
sphin-gomyelinase-induced changes in erythrocyte membrane structure.
Cell Death Dis., 2012, 3(10), e410-e410.
http://dx.doi.org/10.1038/cddis.2012.143 PMID: 23076218
van Zwieten, R.; Bochem, A.E.; Hilarius, P.M.; van Bruggen, R.;
[56]
Bergkamp, F.; Hovingh, G.K.; Verhoeven, A.J The cholesterol
content of the erythrocyte membrane is an important determinant
of phosphatidylserine exposure Biochim Biophys Acta, 2012,
1821(12), 1493-1500.
http://dx.doi.org/10.1016/j.bbalip.2012.08.008 PMID: 22960544
Straat, M.; van Bruggen, R.; de Korte, D.; Juffermans, N.P Red
[57]
blood cell clearance in inflammation Transfus Med Hemother.,
2012, 39(5), 353-361.
http://dx.doi.org/10.1159/000342229 PMID: 23801928
Otogawa, K.; Kinoshita, K.; Fujii, H.; Sakabe, M.; Shiga, R.;
[58]
Nakatani, K.; Ikeda, K.; Nakajima, Y.; Ikura, Y.; Ueda, M.;
Arakawa, T.; Hato, F.; Kawada, N Erythrophagocytosis by liver
macrophages (Kupffer cells) promotes oxidative stress,
inflamma-tion, and fibrosis in a rabbit model of steatohepatitis: implications
for the pathogenesis of human nonalcoholic steatohepatitis Am J.
Pathol., 2007, 170(3), 967-980.
http://dx.doi.org/10.2353/ajpath.2007.060441 PMID: 17322381
Nagahashi, M.; Abe, M.; Sakimura, K.; Takabe, K.; Wakai, T.
[59]
The role of sphingosine-1-phosphate in inflammation and cancer
progressionCancer Science; Blackwell Publishing Ltd, 2018, 109,
pp 3671-8.
Hänel, P.; Andréani, P.; Gräler, M.H Erythrocytes store and
re-[60]
lease sphingosine 1-phosphate in blood FASEB J., 2007, 21(4),
1202-1209.
http://dx.doi.org/10.1096/fj.06-7433com PMID: 17215483
Pappu, R.; Schwab, S.R.; Cornelissen, I.; Pereira, J.P.; Regard,
[61]
J.B.; Xu, Y.; Camerer, E.; Zheng, Y.W.; Huang, Y.; Cyster, J.G.;
Coughlin, S.R Promotion of lymphocyte egress into blood and
lymph by distinct sources of sphingosine-1-phosphate Science,
2007, 316(5822), 295-298.
http://dx.doi.org/10.1126/science.1139221 PMID: 17363629
Xu, R.; Sun, W.; Jin, J.; Obeid, L.M.; Mao, C Role of alkaline
ce-[62]
ramidases in the generation of sphingosine and its phosphate in
erythrocytes FASEB J., 2010, 24(7), 2507-2515.
http://dx.doi.org/10.1096/fj.09-153635 PMID: 20207939
Sun, K.; Zhang, Y.; Bogdanov, M.V.; Wu, H.; Song, A.; Li, J.;
[63]
Dowhan, W.; Idowu, M.; Juneja, H.S.; Molina, J.G.; Blackburn,
M.R.; Kellems, R.E.; Xia, Y Elevated adenosine signaling via
adenosine A2B receptor induces normal and sickle erythrocyte
sphingosine kinase 1 activity Blood, 2015, 125(10), 1643-1652.
http://dx.doi.org/10.1182/blood-2014-08-595751 PMID:
25587035 Knapp, M.; Lisowska, A.; Zabielski, P.; Musiał, W.; Baranowski, [64]
M Sustained decrease in plasma sphingosine-1-phosphate concen-tration and its accumulation in blood cells in acute myocardial
in-farction Prostaglandins Other Lipid Mediat., 2013, 106, 53-61.
http://dx.doi.org/10.1016/j.prostaglandins.2013.10.001 PMID: 24120760
Bode, C.; Sensken, S-C.; Peest, U.; Beutel, G.; Thol, F.; Levkau, [65]
B.; Li, Z.; Bittman, R.; Huang, T.; Tölle, M.; van der Giet, M.; Gräler, M.H Erythrocytes serve as a reservoir for cellular and
ex-tracellular sphingosine 1-phosphate J Cell Biochem., 2010,
109(6), 1232-1243.
http://dx.doi.org/10.1002/jcb.22507 PMID: 20186882 Christensen, P.M.; Bosteen, M.H.; Hajny, S.; Nielsen, L.B.; [66]
Christoffersen, C Apolipoprotein M mediates
sphingosine-1-phos-phate efflux from erythrocytes Sci Rep., 2017, 7(1), 14983.
http://dx.doi.org/10.1038/s41598-017-15043-y PMID: 29118354
Vu, T.M.; Ishizu, A-N.; Foo, J.C.; Toh, X.R.; Zhang, F.; Whee, [67]
D.M.; Torta, F.; Cazenave-Gassiot, A.; Matsumura, T.; Kim, S.; Toh, S.E.S.; Suda, T.; Silver, D.L.; Wenk, M.R.; Nguyen, L.N Mfsd2b is essential for the sphingosine-1-phosphate export in
ery-throcytes and platelets Nature, 2017, 550(7677), 524-528.
http://dx.doi.org/10.1038/nature24053 PMID: 29045386 Kurano, M.; Nishikawa, M.; Kuma, H.; Jona, M.; Yatomi, Y In-[68]
volvement of Band3 in the efflux of sphingosine 1-phosphate
from erythrocytes.PLoS One; Gerós H, editor, 2017, 12, pp.
5-0177543.
Kobayashi, N.; Kobayashi, N.; Yamaguchi, A.; Nishi, T Charac-[69]
terization of the ATP-dependent sphingosine 1-phosphate
trans-porter in rat erythrocytes J Biol Chem., 2009, 284(32),
21192-21200.
http://dx.doi.org/10.1074/jbc.M109.006163 PMID: 19531471 Xiang, H; Lu, Y; Shao, M; Wu, T Lysophosphatidic acid recep-[70]
tors: Biochemical and clinical implications in different diseases
Journal of Cancer , 2020, 11 , 3519 -35
Cripps, M.W.; Soupene, E.; Harken, A.; Kuypers, F Erythrocytes [71]
contain a membrane lysophosphatidic acid acyltransferase that
mo-dulates serum lysophosphatidic acid concentration J Am Coll.
Surg., 2007, 205(3), S34.
http://dx.doi.org/10.1016/j.jamcollsurg.2007.06.287 Neidlinger, N.A.; Larkin, S.K.; Bhagat, A.; Victorino, G.P.; [72]
Kuypers, F.A Hydrolysis of phosphatidylserine-exposing red blood cells by secretory phospholipase A2 generates
lysophospha-tidic acid and results in vascular dysfunction J Biol Chem.,
2006, 281(2), 775-781.
http://dx.doi.org/10.1074/jbc.M505790200 PMID: 16278219 Cripps, M.W.; Ereso, A.Q.; Victorino, G.P.; Harken, A.H.; Sou-[73]
pene, E.; Kuypers, F Lysophosphatidic acid formation in old
packed red blood cells causes post transfusion vascular leak J.
Am Coll Surg., 2008, 207(3), S37.
http://dx.doi.org/10.1016/j.jamcollsurg.2008.06.072 Aoki, J.; Taira, A.; Takanezawa, Y.; Kishi, Y.; Hama, K.; Kishi-[74]
moto, T.; Mizuno, K.; Saku, K.; Taguchi, R.; Arai, H Serum ly-sophosphatidic acid is produced through diverse phospholipase
pathways J Biol Chem., 2002, 277(50), 48737-48744.
http://dx.doi.org/10.1074/jbc.M206812200 PMID: 12354767 Macdonald, D.J.; Boyle, R.M.; Glen, A.C.A.; Horrobin, D.F Cyto-[75]
solic phospholipase A2 type IVA is present in human red cells.
Blood, 2004, 103(9), 3562-3564.
http://dx.doi.org/10.1182/blood-2002-09-2698 PMID: 14726390
Wu, H.; Bogdanov, M.; Zhang, Y.; Sun, K.; Zhao, S.; Song, A.; [76]
Luo, R.; Parchim, N.F.; Liu, H.; Huang, A.; Adebiyi, M.G.; Jin, J.; Alexander, D.C.; Milburn, M.V.; Idowu, M.; Juneja, H.S.; Kellems, R.E.; Dowhan, W.; Xia, Y Hypoxia-mediated impaired
erythrocyte Lands’ Cycle is pathogenic for sickle cell disease Sci.
Rep., 2016, 6, 29637.
http://dx.doi.org/10.1038/srep29637 PMID: 27436223 McGee, J.E.; Fitzpatrick, F.A Erythrocyte-Neutrophil Interac-[77]
tions: Formation of Leukotriene B4 by Transcellular Biosynthesis
Proceedings of the National Academy of Sciences, 1986, 83, pp.
1349-53.
http://dx.doi.org/10.1073/pnas.83.5.1349 Oonishi, T.; Sakashita, K.; Ishioka, N.; Suematsu, N.; Shio, H.; [78]