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J Immunol 2015; 194:5579-5587; ;
doi: 10.4049/jimmunol.1500259
http://www.jimmunol.org/content/194/12/5579
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Copyright © 2015 by The American Association of
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References
Rick Kapur, Anne Zufferey, Eric Boilard and John W.
Semple
The
Brief Reviews
Journal of
Immunology
Nouvelle Cuisine: Platelets Served with Inflammation
Rick Kapur,*,† Anne Zufferey,* Eric Boilard,‡ and John W. Semple*,†,x,{,‖
P
latelets are traditionally described as cellular fragments
derived from megakaryocytes in the bone marrow that
circulate and continually assess the vessel endothelium
for damage (1). A single megakaryocyte can give rise to ∼1000
platelets that are released into the circulation by a process
called proplatelet formation (1). Platelet generation is a highly
regulated and organized process, and platelets are key cellular
players from a functional perspective. Circulating human
platelets are anucleate and have a diameter ∼2–4 mm and
a lifespan of 8–10 d before they are primarily destroyed by
macrophages within the spleen. There, circulating numbers
range from 150 to 400 3 109/l in humans, whereas rodents
have approximately three times as many circulating platelets.
Although anucleate, platelets have several specialized organelles within their cytoplasm, including a granules, dense
*Toronto Platelet Immunobiology Group, Keenan Research Centre for Biomedical
Science, St. Michael’s Hospital, Toronto, Ontario M5B 1W8, Canada; †Canadian
Blood Services, Toronto, Ontario M5B 1W8, Canada; ‡Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de
Québec, Faculté de Médecine de l’Université Laval, Quebec City, Quebec G1V 4G2,
Canada; xDepartment of Pharmacology, University of Toronto, Toronto, Ontario M5B
1W8, Canada; {Department of Medicine, University of Toronto, Toronto, Ontario
M5B 1W8, Canada; and ‖Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5B 1W8, Canada
granules, endosomes, lysosomes, and mitochondria. The a
and dense granules contain different cargos that are responsible for the platelet’s ability to aggregate and activate the
coagulation cascade at the site of vessel injury. Platelets also
have a series of invaginated folded membranes that form the
inner canalicular system, and this allows the platelet to significantly increase surface area upon activation. What has
become clear over the last 50 years is that, in addition to their
primary role in hemostasis, platelets are multifunctional and
are key players in many other physiological and pathological
processes (e.g., wound repair, inflammatory processes, and the
immune response) (2–8).
Interestingly, in many invertebrate life forms, a single cell type
is responsible for multiple innate defense functions, including
hemostasis (9, 10). Further specialization into various blood
cell types occurred by the vertebrate stage, and this eventually
evolved into mammalian anucleate platelets, with both hemostatic and inflammatory properties (9, 10). The relationship
between platelets and inflammation has been suspected for
decades because of observations made from the atherosclerosis
literature (11). Atherosclerosis is a chronic inflammatory process and platelet interactions with, for example, leukocytes and
endothelium represent an important association between inflammation and atherogenesis. This includes platelet activation,
adhesion of platelets to endothelium, and the platelet’s ability
to secrete inflammatory molecules that can alter the chemoattractive, adhesive, and proteolytic properties of endothelial
cells. This can ultimately support the migration and adhesion
of monocytes to the site and facilitate the formation of atherosclerotic plaque. This review briefly outlines some of the
nonhemostatic roles that platelets can play, particularly with
respect to inflammation and immunity. Although it is beyond
the scope of this article to comprehensively discuss all of the
literature, several excellent and comprehensive reviews are cited
to direct the reader to more details on the respective subjects.
Platelets and pathogens
It is well known that platelets can harbor pathogens, including
viruses (12, 13), bacteria (14–16), and parasites (4), on their
Address correspondence and reprint requests to Dr. John W. Semple, St. Michael’s
Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada. E-mail address:
[email protected]
Abbreviations used in this article: CRP, C-reactive protein; DC, dendritic cell; Del-1,
developmental endothelial locus-1; GPVI, glycoprotein VI; ITP, immune thrombocytopenia; NET, neutrophil extracellular trap; PF, platelet factor; PMP, platelet microparticle; PPAR, peroxisome proliferator-activated receptor; PS, phosphatidylserine; RA,
rheumatoid arthritis; sCD40L, soluble form of CD40L; TF, tissue factor; b-TG,
b-thromboglobulin; TPO, thrombopoietin.
Received for publication February 3, 2015. Accepted for publication March 26, 2015.
R.K. is the recipient of a postdoctoral fellowship from the Canadian Blood Services. A.Z.
is the recipient of a postdoctoral fellowship from the Swiss National Science Foundation
(P2GEP3_151966). E.B. is the recipient of a new investigator award from the Canadian
Institutes of Health Research.
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500259
Copyright 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00
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Platelets are small cellular fragments with the primary physiological role of maintaining hemostasis. In
addition to this well-described classical function, it is
becoming increasingly clear that platelets have an intimate connection with infection and inflammation.
This stems from several platelet characteristics, including their ability to bind infectious agents and secrete
many immunomodulatory cytokines and chemokines,
as well as their expression of receptors for various immune effector and regulatory functions, such as TLRs,
which allow them to sense pathogen-associated molecular patterns. Furthermore, platelets contain RNA that
can be nascently translated under different environmental stresses, and they are able to release membrane
microparticles that can transport inflammatory cargo
to inflammatory cells. Interestingly, acute infections can
also result in platelet breakdown and thrombocytopenia. This report highlights these relatively new aspects
of platelets and, thus, their nonhemostatic nature in
an inflammatory setting. The Journal of Immunology,
2015, 194: 5579–5587.
5580
sors within the blood as a result of their expression of several
receptors that have no obvious function in hemostasis.
Platelet TLRs
Platelets express functional immune receptors called pattern
recognition receptors, which include complement receptors
and TLRs (2). These platelet-associated structures allow them
to bind foreign microbial invaders and products derived from
microbes. Thus, infectious binding allows platelets to participate in “danger sensing” (pathogen, or damage in the case of
sterile inflammation) that is typically described for cells of
the innate immune system. Pathogens are thought to be first
encountered by TLRs on professional phagocytes, such as
neutrophils, macrophages, and dendritic cells (DCs) (2, 32,
33). TLRs are germline-encoded proteins that bind a variety
of infectious molecular structures and are critical for stimulating innate immune mechanisms (2, 32, 33). The ligands
of TLRs have been studied extensively, and they range from
secretory components of pathogens to nucleic acids. Many
articles reported that TLRs 1–9 are expressed on both human
and murine platelets, and some of these are functional, such as
TLR4 in the mediation of LPS-induced thrombocytopenia
and TNF-a production in vivo (34–40). Likewise, the previously mentioned platelet–neutrophil interaction leading to
NET formation and subsequent trapping of bacteria during
sepsis is triggered via platelet TLR4 (6). It was suggested that
platelets might be primarily responsible for reactivity against
bacterial products, and it was speculated that platelets act as
circulating sentinels that bind infectious agents and present
them to neutrophils and/or cells of the reticuloendothelial
system (36–40).
Relatively few studies have examined the expression and
function of TLRs on megakaryocytes; however, it was demonstrated that endotoxemia can increase in vivo thrombopoietin (TPO) levels, which was associated with an increase in
circulating young reticulated platelets and enhanced platelet–
neutrophil aggregates (41). Furthermore, bone marrow treated with LPS showed increased levels of TPO, suggesting that
inflammation and infection may have roles to play in platelet
production (42). Related to this, compared with control mice,
TLR4-knockout mice have decreases in circulating platelet
counts and reticulated platelets, suggesting that TLR4 may
have a role in thrombopoiesis (34, 43).
Platelet CD40L (CD154)
In addition to their critical role in costimulation, CD40L
(CD40L/CD154) and CD40 were proposed to play a central role in thrombotic diseases (44). Platelets contain a significant amount of CD40L that is expressed and released
upon platelet activation. Once expressed, platelet CD40L can
interact with membrane-bound CD40 on endothelial cells,
triggering several inflammatory reactions leading to local release of adhesion molecules including, for example, ICAM1,
VCAM1, and CCL2 (45). Upon activation, platelets release
most of their expressed CD40L, producing its soluble form
(sCD40L); the vast majority of sCD40L circulating in the
plasma is derived from activated platelets (46). Upon exposure to CD40-expressing vascular cells (including endothelial
cells), platelet-derived sCD40L can induce the expression of
adhesion molecules, such as E-selectin and P-selectin, and
initiate the release of tissue factor and IL-6 (47, 48). Thus, it
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plasma membrane and internally (3, 13). Platelets are also
known to be involved in acute and chronic liver disease related to hepatitis B virus infection via upregulation of virusspecific CD8+ T cells and nonspecific inflammatory cells into
the liver (17). Furthermore, platelets were implicated in the
clearance of bacterial infections: thrombin-stimulated platelets
facilitated clearance of streptococci in infective endocarditis
(18). In addition, activated platelets were shown to surround
Staphylococcus aureus, thereby inhibiting their bacterial growth
rate via secretion of the antimicrobial peptide b-defensin and
the induction of neutrophil extracellular trap (NET) formation (13, 19), a process that also was described to occur in
other settings, including thrombosis, transfusion-related acute
lung injury, storage of RBCs, and sickle cell disease (20–25).
Interestingly, platelets also were shown to be involved in the
trapping of bacteria (methicillin-resistant S. aureus and Bacillus cereus) on the surface of Kupffer cells in the liver (5). In
this study, GPIba-deficient mice were more prone to endothelial and Kupffer cell damage, with increased vascular
leakage and rapid mortality, than were wild-type mice.
McMorran et al. (4) elegantly showed that activated platelets
can limit the growth of the malarial parasite Plasmodium
falciparum by entering the infected RBC via a platelet factor
(PF)-4– and Duffy Ag-dependent manner. How the platelets
actually kill the internalized parasite is still unknown. Therefore, it is possible that patients with platelet disorders, in which
the aforementioned pathogen-reducing mechanisms would
be compromised, are more susceptible to infections.
Alternatively, the binding of infectious agents to platelets
could contribute to spread of the infection. During sepsis,
activation of platelets can contribute to the development
of disseminated intravascular coagulation, which can subsequently occlude blood vessels, leading to increased ischemia
and multiple organ failure. Additionally, septic platelet activation can facilitate the production of both pro- and antiinflammatory cytokine networks (26). The nature of this
platelet activation is characterized by increased surface Pselectin expression (27, 28); increased levels of a granule–
released factors in plasma, such as soluble P-selectin (29); and
increased levels of triggering receptor expressed on myeloid
cells-like transcript-1 (30) or PF-4 in mice (31). Clark et al.
(6) also showed a novel mechanism of platelet–neutrophil
interaction that leads to enhanced bacterial trapping during
sepsis. Platelet binding stimulated neutrophils to release
NETs, and the extended DNA contributed significantly to
trapping bacteria. Elegant in vivo imaging demonstrated that
the liver sinusoids and lung capillaries where platelets and
neutrophils bound during sepsis were the primary sites of
NET formation (6). Platelet-induced NET formation, although beneficial in trapping bacteria, may also be of detriment because it may occur at the expense of injury to the host.
It appears that when LPS-activated neutrophils bind endothelium, little damage occurs; however, if the bound neutrophils encounter LPS-bearing platelets, they become
significantly activated and release their NETs together with
reactive oxygen species that cause damage to the underlying
endothelium (6). Moreover, Sreeramkumar et al. (7) showed
that neutrophils were able to scan platelets for activation
in the bloodstream through the P-selectin ligand signaling
pathway, leading to inflammation. Currently, there is a wealth
of evidence to suggest that platelets can act as pathogen sen-
BRIEF REVIEWS: PLATELETS AND INFLAMMATION
The Journal of Immunology
Platelet MHC class I
Platelets also harbor MHC class I molecules both on their
plasma membrane and intracellularly (66). On the platelet
plasma membrane, MHC class I molecules are primarily
adsorbed from plasma and generally consist of denatured H
chains. The membrane-bound MHC also appears unstable
because the molecules can passively dissociate from the
platelet upon blood bank storage or can be eluted from the
surface by chloroquine diphosphate or acid washing, without
affecting platelet membrane integrity (67–73). At the allogeneic level, through transfusions, the denatured platelet MHC
class I can evoke faulty interactions with CD8+ T cells, which
appear to anergize CTLs. For example, allogeneic platelet
MHC class I molecules cannot stimulate CTL-mediated cytotoxicity on their own (73) but can mediate the so-called
“transfusion effect,” an immunosuppressive-like response to
transfused blood products. CBA mice transfused with allogeneic BALB/c platelets readily accepted donor-specific skin
grafts compared with nontransfused recipients (74). This
observation supports the concept that allogeneic platelets may
interfere with T cell–mediated cytotoxicity reactions, such as
skin graft rejection. In contrast, more recent data suggest that,
intracellularly, platelet MHC class I molecules are associated
with a granules and are mostly intact integral membrane
proteins associated with b2-microglobulin (75). Moreover,
molecular analysis of platelet proteins revealed that platelets
contain the entire proteasome system, together with TAP
molecules; however, they lack endoplasmic reticulum. It
now appears that, in syngeneic systems, activated platelets
can express nascent MHC class I molecules, and these have
the ability to present Ags to CD8+ T cells. Chapman et al.
(76) elegantly demonstrated that activated platelets can
present malarial peptides to malaria-specific T cells, and this
leads to an enhanced immunity against the parasite. Thus,
depending on the source of MHC (surface bound or internalized), platelets can mediate either T cell suppression
or activation.
Platelet cytokines/chemokines
Platelets carry a plethora of chemokine and cytokine cargo that
can play roles in diverse processes associated with hemostatic
functions and wound repair (77), as well as with proinflammatory and anti-inflammatory processes, such as TGF-b,
a potent immunosuppressive factor (78). Although the physiological role of large amounts of TGF-b in platelets (78) is
unclear, platelets appear to regulate blood levels of TGF-b. For
example, in patients with immune thrombocytopenia (ITP),
low levels of TGF-b were observed in active disease but these
levels normalized concomitantly with increasing platelet
counts upon treatment (79, 80). Most of the chemokines and
cytokines are found within the various platelet granules. For
example, the a granules contain several immunomodulatory
soluble factors, such as chemokines, including PF (CXCL4),
b-thromboglobulin (b-TG; an isoform of CXCL7), RANTES
(CCL5), and MIP-1a (CCL3) (81). When released upon
platelet activation, these chemokines can mediate a diverse
array of cellular interactions. For example, platelet PF-4 can
render monocytes resistant to apoptosis and induce their differentiation into macrophages (82). In addition, PF-4 can
enhance neutrophil adhesion to unstimulated endothelium
and granule content release (83). In contrast, platelet-derived
b-TGs, which are proteolytic products of inactive precursors,
can have either stimulatory or inhibitory activity for neutrophils (84). Finally, platelet-derived MIP-1a can stimulate
the release of histamine from basophils (85) and is chemotactic for T cells (86).
Platelet transcriptomics
Platelets express an enormous number of different molecules,
many of which can be secreted during platelet activation via
various regulated pathways (81, 87–89). These molecules in
platelets may come from different sources, such as those
inherited from megakaryocytes, those absorbed from the
plasma, or those generated de novo. With regard to de novo
synthesis of molecules in platelets, although platelets are
anucleate, they express significant amounts of RNA, including
mRNAs (e.g., premature and mature RNA), structural and
catalytic RNAs (e.g., ribosomal and tRNA), regulatory RNAs
(e.g., microRNA), and noncoding RNA (e.g., anti-sense
RNA) (90–105). More recently, it also was revealed that
platelets contain all of the molecular machinery to translate
mRNA into proteins, and they have the ability to transfer
RNA to recipient cells where it can regulate cellular function
(101–104). However, it should be noted that the content
of platelet RNA transcript does not fully correspond to the
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is becoming increasingly clear that the platelet CD40L–
CD40 axis may play a central link between the endothelium/
coagulation and inflammation.
Platelet-derived CD40L also was shown to enhance CD8+
T cell responses and to promote T cell responses postinfection
with Listeria monocytogenes (49, 50), thereby bridging the gap
between innate and adaptive immunity. Such studies extend
platelet function to modulation of innate and adaptive immunity through, for example, release of chemokines, cytokines, and immunomodulatory ligands, including CD40L,
and showed that platelets, via CD40L, can induce DC maturation (51). With respect to the latter, it appears that platelets can bind DCs in a CD40L-dependent manner and
significantly affect their differentiation and activation. For
example, Kissel et al. (51) showed that activated platelets
could impair DC differentiation, suppress proinflammatory
cytokines IL-12p70 and TNF by DCs, and increase the
production of IL-10 by DCs. These types of platelet–DC
interactions could potentially affect adaptive immune responses. In addition, activated platelets can augment lymphocyte
adhesion to the endothelium (52) and facilitate lymphocyte
homing in high endothelial venules (53) and migration into
inflammatory regions. Furthermore, platelets can facilitate B
cell differentiation and Ab class switching because of their
large content of CD40L (54, 55). A nongenomic role for NFkB was shown to be important as well, because the CD40L–
CD40 axis was demonstrated to trigger NF-kB activation in
platelets (56). Also, there have been several reports supporting
both positive and negative pathways of platelet activation
involving NF-kB signaling cascades (57–61), as well as
platelet pathways involving other nuclear receptors, such as
peroxisome proliferator-activated receptors (PPARs) (62–64)
and retinoid X receptors (65). Thus, there are several possible
avenues by which platelets can modulate adaptive immune
mechanisms through interactions with their CD40L and/or
sCD40L derived from platelets.
5581
5582
BRIEF REVIEWS: PLATELETS AND INFLAMMATION
content of the platelet proteome (106). These molecular
attributes of platelets have opened up an entirely new field of
platelet genetics, and Schubert et al. (107) provided an excellent recent review on platelet mRNA and its impact on
platelet function during health and disease.
Platelet microparticles
Pioneer investigations revealed “dust” liberated by platelets
upon activation that is capable of supporting thrombin generation, even in the absence of intact platelets (108). Platelet
dust, now known as microparticles (also called microvesicles),
are small extracellular vesicles produced by cell cytoplasmic
blebbing and fission. Microparticles are ∼100–1000 nm in
diameter, although the majority seem to be ∼200 nm in size
and are distinct from exosomes, which have smaller dimensions (∼50–100 nm in diameter) and originate from multivesicular bodies through exocytosis (109). The minimal
experimental requirements for defining extracellular vesicles
Nonhemostatic roles of platelets in infection and inflammation
Pathogen Reduction
Harboring of pathogens (viruses, bacteria, and parasites) (3, 4, 12–16)
Clearance of bacterial infections (18)
Inhibiting growth of S. aureus via b-defensin and NET induction (19)
Bacterial trapping on surface Kupffer cells (5) and via hepatic and pulmonary NETs during sepsis (20)
Growth inhibition of malarial parasites via erythrocyte invasion (4)
Platelet TLRs
Pathogen detection (2)
TLR4: LPS-induced thrombocytopenia and TNF-a production (36), bacterial trapping via NETs in sepsis (6), possible role in thrombopoiesis (34, 43)
Platelet CD40L (CD154)
Inflammatory reactions via interaction with CD40 of vascular cells: release of adhesion molecules (45, 47, 48)
Triggering of T cell responses postinfection with L. monocytogenes (49, 50)
Binding of DCs: impairment of DC differentiation (51), suppression of DC proinflammatory cytokines (51), increase in DC IL-10 production (51)
Induction of B cell differentiation and Ab class-switching (54, 55)
Triggering of NF-kB activation in platelets (56)
Platelet MHC Class I
Intracellular MHC class I association with platelet a granules (75)
Presence of proteasome system with TAP molecules in platelets (75)
Platelet presentation of malarial peptides to malaria T cells: enhanced immunity toward parasite (76)
Platelet Cytokine/Chemokines
Many chemokines and cytokines involved in pro/anti-inflammatory pathways, including the immunosuppressant TGF-b, as well as chemokines PF-4,
b-TG, RANTES, MIP-1a (81). For overview, see Ref. 2.
Platelet Transcriptomics
De novo synthesis of platelet molecules: significant amount of RNA (90–104), contain molecular machinery for mRNA translation and ability to transfer
RNA to other cells to regulate cellular function (101–104)
Impact on health and disease (reviewed in Ref. 107)
PMPs
Platelet activation via GPVI in autoimmune inflammatory arthritis forms PMPs (8)
LPS stimulation of platelet TLR4 forms PMPs in sepsis (125)
Increased IL-1 in PMPs indicates role in inflammation (8, 125)
Immune complexed bacterial components and epitopes of influenza viruses form PMPs via FcgRIIa (126, 127)
PMPs implicated in cell–cell communications via integrin, lactaderhin, and Del-1 (131, 132)
PMP cargo consists of cytokines, chemokines, lipid mediators, enzymes, receptors, nucleic acids, autoantigens, transcription factors, mitochondria (103,
117–119, 128–130)
Platelet Breakdown
Cross-reactive autoantibodies due to molecular mimicry between viral/bacterial Ags and platelet Ags (135–139)
H. pylori ITP increased platelet count after eradication of H. pylori (140)
LPS enhancement of Ab-mediated platelet clearance in vitro and in vivo (37, 141)
CRP enhancement of Ab-mediated platelet clearance in vitro and in vivo (142)
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Table I.
and their functions were published by the International Society for Extracellular Vesicles (110).
Although the shedding of microparticles is not unique to
platelets, they are particularly potent in this process. Hence,
recent examination of human plasma using cryotransmission
electron microscopy and gold nanospheres conjugated to Abs
directed against the platelet marker CD41 confirmed that
microparticles of platelet origin are the most abundant in
circulation (111). The formation of microparticles appears to
be associated with increased intracellular calcium levels, cytoskeletal rearrangement, and loss of membrane asymmetry
resulting in phosphatidylserine (PS) exposure on their surface
(112). The exposed PS, given its anionic properties, supports
blood coagulation, although microparticles derived from
platelets express modest levels of tissue factor (TF) and appear
less procoagulant that do monocyte-derived microparticles,
which express both PS and TF (113). In a recent study,
Tersteeg et al. (114) elegantly examined platelet activation
The Journal of Immunology
under physiological flow and observed extremely long (up to
250 mm) membrane strands emerging from platelets, which is
substantial considering their small size. These strands, called
flow-induced protrusions, also expose PS, recruit neutrophils
and monocytes (and not platelets), and appear to break off
into PS+ microparticles (114). Intriguingly, studies also shed
light on PS2 microparticles in body fluids (111, 115–117),
5583
pointing to the heterogeneity of the microparticles produced
by platelets.
The small dimensions of microparticles represent a challenge
for the proper assessment of their expression in biological
fluids. Primarily using flow cytofluorometry methodologies,
platelet-derived microparticles have been observed in different
inflammatory conditions in which platelets are activated (118,
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FIGURE 1. The key roles of platelets in modulating inflammatory processes. (1) Platelets can uptake infectious agents, and via the expression of TLRs they
can activate neutrophils to, for example, secrete NETs. (2) Platelet CD40L expression allows them to interact with different cells of the immune system and
either activate (arrows) and/or suppress (T bar) them. (3) Intact platelet MHC class I molecules are located intracellularly but upon activation are expressed
and can activate Ag (e.g., malaria)-specific CD8+ T cells. In contrast, the MHC class I molecules on the surface of resting platelets are denatured and lead to
CD8+ T cell inhibition. (4) Platelets release PMPs under a variety of stress conditions, and these PMPs can carry multiple cargos to other cells and sites of
inflammation. (5) Platelets contain many proinflammatory and anti-inflammatory cytokines and chemokines and, upon activation, can release them to the
extracellular space. (6) Immune interactions with platelets can lead to severe thrombocytopenic states, such as in the case of sepsis, where infections can bind
to platelets and cause their sequestration and/or destruction or ITP, where the combination of Ab and infectious particles or CRP leads to increased platelet destruction. (7) Platelets contain several species of RNA, and these can be exported via PMPs or mRNAs can be translated into nascent protein synthesis. The culmination
of these events makes platelets a formidable immunomodulatory host.
5584
Infections and thrombocytopenia
In addition to being suppressed by platelets, acute viral or
bacterial infections can often lead to low platelet counts or
thrombocytopenia, which might be a viral or bacterial strategy
to evade immune responses. The production of platelets is
highly regulated, because this is important to prevent serious
bleeding when platelet counts are low, as well as to prevent
vascular occlusion and organ damage when platelet counts are
increased. Recently, it was elegantly shown that platelet production can be regulated by binding of desialylated platelets to
the hepatic Ashwell–Morell receptor, which induces expression of TPO in the liver via JAK2-STAT3 signaling (133).
Acute bacterial or viral infections are known to potentiate
ITP, an autoimmune bleeding disorder in which platelets are
targeted (134). The pathophysiological mechanism of acute
infection–associated destruction of platelets is incompletely
understood, but several likely scenarios have been suggested.
One of them is molecular mimicry between viral/bacterial
Ags and platelet Ags, leading to the production of autoantibodies that cross-react (135–139). Also, several patients with
Helicobacter pylori (Gram-negative bacterium)–related ITP
exhibited increased platelet count following H. pylori–eradication therapy (140). In line with this, LPS, a Gram-negative
bacterial endotoxin, enhanced FcgR-mediated phagocytosis
of anti-platelet Ab–opsonized platelets in vitro (37), as well
as a potent synergistic effect of anti-platelet Abs and LPS,
resulting in platelet clearance in vivo (141). Therefore, LPS
may be an important mediator of Ab-mediated platelet clearance during Gram-negative infections; despite not knowing
the exact working mechanism, triggering of phagocyte and/or
platelet TLR4 could be relevant. Recently, C-reactive protein (CRP) was identified as a novel pathogenic serum factor
that enhances IgG-mediated platelet destruction in vitro and
in vivo (142). CRP is an acute-phase protein, also present in
healthy individuals, which increases rapidly during acute infections. CRP was found to be increased in children with ITP,
and treatment with IVIg was associated with increased platelet
counts, decreased CRP levels, and reduced clinical bleeding
severity (142). Moreover, elevated CRP at diagnosis corresponded to slower platelet count recovery after 3 mo (142).
The suggested mechanism of action was independent of
platelet FcgRIIA but based on platelet oxidation (triggered
by anti-platelet Abs and the phagocyte NADPH oxidase system), which resulted in exposure of platelet phosphorylcholine residues to which CRP could bind and, thereby, enhance
IgG-mediated platelet phagocytosis via interaction with phagocytic FcRs (142). Therefore, CRP could be an important factor in Ab-mediated platelet destruction in bacterial (Gramnegative and/or Gram-positive) or viral infections associated
with ITP.
A summary of all the above-mentioned characteristics is
shown in Table I and illustrated in Fig. 1.
Conclusions
Platelets are best known as primary mediators of hemostasis
and thrombin generation; however, like leukocytes, they have
multiple functions related to inflammation/immunity. It appears that these anucleate cellular fragments express and secrete
several diverse pro- and anti-inflammatory molecules that serve
to initiate and modulate immune functions. These aspects of
platelets and immunity have initiated a new understanding of
the role of platelets in infectious processes and how they can
significantly modulate the immune system.
Disclosures
The authors have no financial conflicts of interest.
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119), and their levels often correlate with disease progression.
For instance, levels of platelet-derived microparticles are increased in blood and synovial fluid of patients affected with
rheumatoid arthritis (RA), the most common autoimmune
joint disorder (8, 120–123). Consistently, different groups
found that platelet depletion in a murine model of RA
attenuates inflammation (8, 124). Although microparticles are
found in sterile, as well as in infectious, inflammatory disorders, it is often not clear what platelet trigger is behind their
release. Multiple activation pathways might promote the
generation of microparticles in inflammation, such as high
shear forces, platelet receptor activation, and apoptosis. In
RA, the activation of platelets through the collagen receptor
glycoprotein VI (GPVI) induces the formation of microparticles, whereas in sepsis, microparticles can be produced via
the stimulation of platelet TLR-4 by bacterial LPS (8, 125).
Interestingly, the microparticles shed through both signals
(GPVI and TLR-4) are rich in IL-1, pointing to their role in
amplification of inflammation (8, 125). Platelets also participate in adaptive immunity through stimulation of FcgRIIA.
Indeed, in immunized subjects, bacterial components and
well-conserved epitopes expressed by influenza viruses are
capable of forming immune complexes that activate FcgRIIA
(126, 127), leading to the formation of microparticles.
Functionally, platelet microparticles (PMPs) are thought to
participate in cell–cell communication. The PMP cargo is vast
and includes cytokines and chemokines (e.g., IL-1, RANTES),
potent lipid mediators (e.g., thromboxane A2), functional
enzymes (e.g., inducible NO synthase), surface receptors (e.g.,
CD40L), nucleic acids (e.g., microRNA), autoantigens (e.g.,
citrullinated fibrinogen), transcription factors (e.g., PPARg,
RuvB-like2, STAT3, STAT5a), and even respiratory-competent mitochondria, all of them potentially having an impact
on the cell targeted by microparticles (103, 117–119, 128–
130). Because they express surface receptors and PS (although
some are PS2), microparticles interact with other cells through
integrin and via the PS-binding proteins lactaderhin (131)
and developmental endothelial locus-1 (Del-1) (132). Hence,
lactaderhin2/2 and Del-12/2 mice express higher levels of
plasma microparticles compared with their wild-type counterparts, suggesting that these proteins are involved in microparticle clearance and in microparticle interaction with other
cells (131, 132). Transcription factors packaged inside PMPs
can enable transcellular effects, such as PPARg, which was
shown to be transported into PMPs and transferred to monocytes where it elicited transcellular effects (129). However, it is
unknown whether specific internalization signals exist beyond
the initial contact of microparticles with the cellular recipient.
Thus, microparticles can contribute to the dissemination of
inflammatory signals derived from platelets. Furthermore, given
that they are induced in several inflammatory pathologies,
microparticles appear to be potent biomarkers. Understanding
the molecular mechanisms implicated in microparticle functions
and improvements in their assessment will contribute to the
delineation of their physio(patho)logical roles.
BRIEF REVIEWS: PLATELETS AND INFLAMMATION
The Journal of Immunology
5585
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