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Nouvelle Cuisine: Served with Inflammation x { ‖ Rick Kapur,*,† Anne Zufferey,* Eric Boilard,‡ and John W. Semple*,†, , , Platelets are small cellular fragments with the pri- granules, endosomes, lysosomes, and mitochondria. The a mary physiological role of maintaining hemostasis. In and dense granules contain different cargos that are respon- addition to this well-described classical function, it is sible for the ’s ability to aggregate and activate the becoming increasingly clear that platelets have an in- cascade at the site of vessel injury. Platelets also timate connection with infection and inflammation. have a series of invaginated folded membranes that form the This stems from several platelet characteristics, includ- inner canalicular system, and this allows the platelet to sig- ing their ability to bind infectious agents and secrete nificantly increase surface area upon activation. What has many immunomodulatory and , become clear over the last 50 years is that, in addition to their as well as their expression of receptors for various im- primary role in hemostasis, platelets are multifunctional and mune effector and regulatory functions, such as TLRs, are key players in many other physiological and pathological which allow them to sense pathogen-associated molec- processes (e.g., wound repair, inflammatory processes, and the immune response) (2–8). ular patterns. Furthermore, platelets contain RNA that Interestingly, in many invertebrate life forms, a single cell type can be nascently translated under different environ- is responsible for multiple innate defense functions, including mental stresses, and they are able to release membrane hemostasis (9, 10). Further specialization into various blood microparticles that can transport inflammatory cargo cell types occurred by the vertebrate stage, and this eventually to inflammatory cells. Interestingly, acute infections can evolved into mammalian anucleate platelets, with both he- also result in platelet breakdown and thrombocytope- mostatic and inflammatory properties (9, 10). The relationship nia. This report highlights these relatively new aspects between platelets and inflammation has been suspected for of platelets and, thus, their nonhemostatic nature in decades because of observations made from the atherosclerosis an inflammatory setting. The Journal of Immunology, literature (11). Atherosclerosis is a chronic inflammatory pro- 2015, 194: 5579–5587. cess and platelet interactions with, for example, leukocytes and endothelium represent an important association between in- flammation and atherogenesis. This includes platelet activation, latelets are traditionally described as cellular fragments

by guest on October 1, 2021. Copyright 2015 Pageant Media Ltd. adhesion of platelets to endothelium, and the platelet’s ability derived from in the bone marrow that to secrete inflammatory molecules that can alter the chemo- circulate and continually assess the vessel endothelium P attractive, adhesive, and proteolytic properties of endothelial for damage (1). A single can give rise to ∼1000 cells. This can ultimately support the migration and adhesion platelets that are released into the circulation by a process of to the site and facilitate the formation of ath- called proplatelet formation (1). Platelet generation is a highly erosclerotic plaque. This review briefly outlines some of the regulated and organized process, and platelets are key cellular nonhemostatic roles that platelets can play, particularly with players from a functional perspective. Circulating human respect to inflammation and immunity. Although it is beyond ∼ platelets are anucleate and have a diameter 2–4 mm and the scope of this article to comprehensively discuss all of the http://classic.jimmunol.org a lifespan of 8–10 d before they are primarily destroyed by literature, several excellent and comprehensive reviews are cited macrophages within the spleen. There, circulating numbers to direct the reader to more details on the respective subjects. range from 150 to 400 3 109/l in humans, whereas rodents have approximately three times as many circulating platelets. Platelets and pathogens Although anucleate, platelets have several specialized organ- It is well known that platelets can harbor pathogens, including elles within their cytoplasm, including a granules, dense viruses (12, 13), bacteria (14–16), and parasites (4), on their Downloaded from

*Toronto Platelet Immunobiology Group, Keenan Research Centre for Biomedical Address correspondence and reprint requests to Dr. John W. Semple, St. Michael’s Science, St. Michael’s Hospital, Toronto, Ontario M5B 1W8, Canada; †Canadian Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada. E-mail address: Blood Services, Toronto, Ontario M5B 1W8, Canada; ‡Centre de Recherche en Rhu- [email protected] matologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de Abbreviations used in this article: CRP, C-reactive ; DC, dendritic cell; Del-1, Que´bec, Faculte´ de Me´decine de l’Universite´ Laval, Quebec City, Quebec G1V 4G2, x developmental endothelial locus-1; GPVI, VI; ITP, immune thrombocy- Canada; Department of Pharmacology, University of Toronto, Toronto, Ontario M5B { topenia; NET, extracellular trap; PF, platelet factor; PMP, platelet micropar- 1W8, Canada; Department of Medicine, University of Toronto, Toronto, Ontario ‖ ticle; PPAR, peroxisome proliferator-activated receptor; PS, phosphatidylserine; RA, M5B 1W8, Canada; and Department of Laboratory Medicine and Pathobiology, Uni- rheumatoid arthritis; sCD40L, soluble form of CD40L; TF, tissue factor; b-TG, versity of Toronto, Toronto, Ontario M5B 1W8, Canada b-thromboglobulin; TPO, . 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. Copyright 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 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 5580 BRIEF REVIEWS: PLATELETS AND

plasma membrane and internally (3, 13). Platelets are also sors within the blood as a result of their expression of several known to be involved in acute and chronic liver disease re- receptors that have no obvious function in hemostasis. lated to hepatitis B virus infection via upregulation of virus- specific CD8+ T cells and nonspecific inflammatory cells into Platelet TLRs the liver (17). Furthermore, platelets were implicated in the Platelets express functional immune receptors called pattern clearance of bacterial infections: thrombin-stimulated platelets recognition receptors, which include complement receptors facilitated clearance of streptococci in infective endocarditis and TLRs (2). These platelet-associated structures allow them (18). In addition, activated platelets were shown to surround to bind foreign microbial invaders and products derived from Staphylococcus aureus, thereby inhibiting their bacterial growth microbes. Thus, infectious binding allows platelets to partic- rate via secretion of the antimicrobial peptide b-defensin and ipate in “danger sensing” (pathogen, or damage in the case of the induction of neutrophil extracellular trap (NET) forma- sterile inflammation) that is typically described for cells of tion (13, 19), a process that also was described to occur in the innate immune system. Pathogens are thought to be first other settings, including thrombosis, transfusion-related acute encountered by TLRs on professional phagocytes, such as lung injury, storage of RBCs, and sickle cell disease (20–25). , macrophages, and dendritic cells (DCs) (2, 32, Interestingly, platelets also were shown to be involved in the 33). TLRs are germline-encoded that bind a variety trapping of bacteria (methicillin-resistant S. aureus and Ba- of infectious molecular structures and are critical for stimu- cillus cereus) on the surface of Kupffer cells in the liver (5). In lating innate immune mechanisms (2, 32, 33). The ligands this study, GPIba-deficient mice were more prone to endo- of TLRs have been studied extensively, and they range from thelial and Kupffer cell damage, with increased vascular secretory components of pathogens to nucleic acids. Many leakage and rapid mortality, than were wild-type mice. articles reported that TLRs 1–9 are expressed on both human McMorran et al. (4) elegantly showed that activated platelets and murine platelets, and some of these are functional, such as can limit the growth of the malarial parasite TLR4 in the mediation of LPS-induced thrombocytopenia falciparum by entering the infected RBC via a platelet factor and TNF-a production in vivo (34–40). Likewise, the pre- (PF)-4– and Duffy Ag-dependent manner. How the platelets viously mentioned platelet–neutrophil interaction leading to actually kill the internalized parasite is still unknown. There- NET formation and subsequent trapping of bacteria during fore, it is possible that patients with platelet disorders, in which sepsis is triggered via platelet TLR4 (6). It was suggested that the aforementioned pathogen-reducing mechanisms would platelets might be primarily responsible for reactivity against be compromised, are more susceptible to infections. bacterial products, and it was speculated that platelets act as Alternatively, the binding of infectious agents to platelets circulating sentinels that bind infectious agents and present could contribute to spread of the infection. During sepsis, them to neutrophils and/or cells of the reticuloendothelial activation of platelets can contribute to the development system (36–40). of disseminated intravascular coagulation, which can subse- Relatively few studies have examined the expression and quently occlude blood vessels, leading to increased ischemia function of TLRs on megakaryocytes; however, it was dem- by guest on October 1, 2021. Copyright 2015 Pageant Media Ltd. and multiple organ failure. Additionally, septic platelet acti- onstrated that endotoxemia can increase in vivo thrombo- vation can facilitate the production of both pro- and anti- poietin (TPO) levels, which was associated with an increase in inflammatory networks (26). The nature of this circulating young reticulated platelets and enhanced platelet– platelet activation is characterized by increased surface P- neutrophil aggregates (41). Furthermore, bone marrow trea- selectin expression (27, 28); increased levels of a granule– ted with LPS showed increased levels of TPO, suggesting that released factors in plasma, such as soluble P-selectin (29); and inflammation and infection may have roles to play in platelet increased levels of triggering receptor expressed on myeloid production (42). Related to this, compared with control mice, cells-like transcript-1 (30) or PF-4 in mice (31). Clark et al. TLR4-knockout mice have decreases in circulating platelet http://classic.jimmunol.org (6) also showed a novel mechanism of platelet–neutrophil counts and reticulated platelets, suggesting that TLR4 may interaction that leads to enhanced bacterial trapping during have a role in thrombopoiesis (34, 43). sepsis. Platelet binding stimulated neutrophils to release NETs, and the extended DNA contributed significantly to Platelet CD40L (CD154) trapping bacteria. Elegant in vivo imaging demonstrated that In addition to their critical role in costimulation, CD40L the liver sinusoids and lung capillaries where platelets and (CD40L/CD154) and CD40 were proposed to play a cen- Downloaded from neutrophils bound during sepsis were the primary sites of tral role in thrombotic diseases (44). Platelets contain a sig- NET formation (6). Platelet-induced NET formation, al- nificant amount of CD40L that is expressed and released though beneficial in trapping bacteria, may also be of detri- upon platelet activation. Once expressed, platelet CD40L can ment because it may occur at the expense of injury to the host. interact with membrane-bound CD40 on endothelial cells, It appears that when LPS-activated neutrophils bind endo- triggering several inflammatory reactions leading to local re- thelium, little damage occurs; however, if the bound neu- lease of adhesion molecules including, for example, ICAM1, trophils encounter LPS-bearing platelets, they become VCAM1, and CCL2 (45). Upon activation, platelets release significantly activated and release their NETs together with most of their expressed CD40L, producing its soluble form reactive oxygen species that cause damage to the underlying (sCD40L); the vast majority of sCD40L circulating in the endothelium (6). Moreover, Sreeramkumar et al. (7) showed plasma is derived from activated platelets (46). Upon expo- that neutrophils were able to scan platelets for activation sure to CD40-expressing vascular cells (including endothelial in the bloodstream through the P-selectin ligand signaling cells), platelet-derived sCD40L can induce the expression of pathway, leading to inflammation. Currently, there is a wealth adhesion molecules, such as E-selectin and P-selectin, and of evidence to suggest that platelets can act as pathogen sen- initiate the release of tissue factor and IL-6 (47, 48). Thus, it The Journal of Immunology 5581

is becoming increasingly clear that the platelet CD40L– proteins associated with b2-microglobulin (75). Moreover, CD40 axis may play a central link between the endothelium/ molecular analysis of platelet proteins revealed that platelets coagulation and inflammation. contain the entire proteasome system, together with TAP Platelet-derived CD40L also was shown to enhance CD8+ molecules; however, they lack endoplasmic reticulum. It T cell responses and to promote T cell responses postinfection now appears that, in syngeneic systems, activated platelets with Listeria monocytogenes (49, 50), thereby bridging the gap can express nascent MHC class I molecules, and these have between innate and adaptive immunity. Such studies extend the ability to present Ags to CD8+ T cells. Chapman et al. platelet function to modulation of innate and adaptive im- (76) elegantly demonstrated that activated platelets can munity through, for example, release of chemokines, cyto- present malarial peptides to malaria-specific T cells, and this kines, and immunomodulatory ligands, including CD40L, leads to an enhanced immunity against the parasite. Thus, and showed that platelets, via CD40L, can induce DC mat- depending on the source of MHC (surface bound or in- uration (51). With respect to the latter, it appears that pla- ternalized), platelets can mediate either T cell suppression telets can bind DCs in a CD40L-dependent manner and or activation. significantly affect their differentiation and activation. For example, Kissel et al. (51) showed that activated platelets Platelet cytokines/chemokines could impair DC differentiation, suppress proinflammatory Platelets carry a plethora of and cytokine cargo that cytokines IL-12p70 and TNF by DCs, and increase the can play roles in diverse processes associated with hemostatic production of IL-10 by DCs. These types of platelet–DC functions and wound repair (77), as well as with proin- interactions could potentially affect adaptive immune respon- flammatory and anti-inflammatory processes, such as TGF-b, ses. In addition, activated platelets can augment lymphocyte a potent immunosuppressive factor (78). Although the phys- adhesion to the endothelium (52) and facilitate lymphocyte iological role of large amounts of TGF-b in platelets (78) is homing in high endothelial venules (53) and migration into unclear, platelets appear to regulate blood levels of TGF-b.For inflammatory regions. Furthermore, platelets can facilitate B example, in patients with immune thrombocytopenia (ITP), cell differentiation and Ab class switching because of their low levels of TGF-b were observed in active disease but these large content of CD40L (54, 55). A nongenomic role for NF- levels normalized concomitantly with increasing platelet kB was shown to be important as well, because the CD40L– counts upon treatment (79, 80). Most of the chemokines and CD40 axis was demonstrated to trigger NF-kB activation in cytokines are found within the various platelet granules. For platelets (56). Also, there have been several reports supporting example, the a granules contain several immunomodulatory both positive and negative pathways of platelet activation soluble factors, such as chemokines, including PF (CXCL4), involving NF-kB signaling cascades (57–61), as well as b-thromboglobulin (b-TG; an isoform of CXCL7), RANTES platelet pathways involving other nuclear receptors, such as (CCL5), and MIP-1a (CCL3) (81). When released upon peroxisome proliferator-activated receptors (PPARs) (62–64) platelet activation, these chemokines can mediate a diverse and retinoid X receptors (65). Thus, there are several possible array of cellular interactions. For example, platelet PF-4 can by guest on October 1, 2021. Copyright 2015 Pageant Media Ltd. avenues by which platelets can modulate adaptive immune render monocytes resistant to apoptosis and induce their dif- mechanisms through interactions with their CD40L and/or ferentiation into macrophages (82). In addition, PF-4 can sCD40L derived from platelets. enhance neutrophil adhesion to unstimulated endothelium and granule content release (83). In contrast, platelet-derived Platelet MHC class I b-TGs, which are proteolytic products of inactive precursors, Platelets also harbor MHC class I molecules both on their can have either stimulatory or inhibitory activity for neu- plasma membrane and intracellularly (66). On the platelet trophils (84). Finally, platelet-derived MIP-1a can stimulate plasma membrane, MHC class I molecules are primarily the release of histamine from basophils (85) and is chemo- http://classic.jimmunol.org adsorbed from plasma and generally consist of denatured H tactic for T cells (86). chains. The membrane-bound MHC also appears unstable because the molecules can passively dissociate from the Platelet transcriptomics platelet upon blood bank storage or can be eluted from the Platelets express an enormous number of different molecules, surface by chloroquine diphosphate or acid washing, without many of which can be secreted during platelet activation via affecting platelet membrane integrity (67–73). At the alloge- various regulated pathways (81, 87–89). These molecules in Downloaded from neic level, through transfusions, the denatured platelet MHC platelets may come from different sources, such as those class I can evoke faulty interactions with CD8+ T cells, which inherited from megakaryocytes, those absorbed from the appear to anergize CTLs. For example, allogeneic platelet plasma, or those generated de novo. With regard to de novo MHC class I molecules cannot stimulate CTL-mediated cy- synthesis of molecules in platelets, although platelets are totoxicity on their own (73) but can mediate the so-called anucleate, they express significant amounts of RNA, including “transfusion effect,” an immunosuppressive-like response to mRNAs (e.g., premature and mature RNA), structural and transfused blood products. CBA mice transfused with allo- catalytic RNAs (e.g., ribosomal and tRNA), regulatory RNAs geneic BALB/c platelets readily accepted donor-specific skin (e.g., microRNA), and noncoding RNA (e.g., anti-sense grafts compared with nontransfused recipients (74). This RNA) (90–105). More recently, it also was revealed that observation supports the concept that allogeneic platelets may platelets contain all of the molecular machinery to translate interfere with T cell–mediated cytotoxicity reactions, such as mRNA into proteins, and they have the ability to transfer skin graft rejection. In contrast, more recent data suggest that, RNA to recipient cells where it can regulate cellular function intracellularly, platelet MHC class I molecules are associated (101–104). However, it should be noted that the content with a granules and are mostly intact integral membrane of platelet RNA transcript does not fully correspond to the 5582 BRIEF REVIEWS: PLATELETS AND INFLAMMATION

content of the platelet proteome (106). These molecular and their functions were published by the International So- attributes of platelets have opened up an entirely new field of ciety for Extracellular Vesicles (110). platelet genetics, and Schubert et al. (107) provided an ex- Although the shedding of microparticles is not unique to cellent recent review on platelet mRNA and its impact on platelets, they are particularly potent in this process. Hence, platelet function during health and disease. recent examination of human plasma using cryotransmission electron microscopy and gold nanospheres conjugated to Abs Platelet microparticles directed against the platelet marker CD41 confirmed that Pioneer investigations revealed “dust” liberated by platelets microparticles of platelet origin are the most abundant in upon activation that is capable of supporting thrombin gen- circulation (111). The formation of microparticles appears to eration, even in the absence of intact platelets (108). Platelet be associated with increased intracellular calcium levels, cy- dust, now known as microparticles (also called microvesicles), toskeletal rearrangement, and loss of membrane asymmetry are small extracellular vesicles produced by cell cytoplasmic resulting in phosphatidylserine (PS) exposure on their surface blebbing and fission. Microparticles are ∼100–1000 nm in (112). The exposed PS, given its anionic properties, supports diameter, although the majority seem to be ∼200 nm in size blood coagulation, although microparticles derived from and are distinct from exosomes, which have smaller dimen- platelets express modest levels of tissue factor (TF) and appear sions (∼50–100 nm in diameter) and originate from multi- less procoagulant that do -derived microparticles, vesicular bodies through exocytosis (109). The minimal which express both PS and TF (113). In a recent study, experimental requirements for defining extracellular vesicles Tersteeg et al. (114) elegantly examined platelet activation

Table I. 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)

by guest on October 1, 2021. Copyright 2015 Pageant Media Ltd. 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)

http://classic.jimmunol.org 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) Downloaded from 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 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) The Journal of Immunology 5583

under physiological flow and observed extremely long (up to pointing to the heterogeneity of the microparticles produced 250 mm) membrane strands emerging from platelets, which is by platelets. substantial considering their small size. These strands, called The small dimensions of microparticles represent a challenge flow-induced protrusions, also expose PS, recruit neutrophils for the proper assessment of their expression in biological and monocytes (and not platelets), and appear to break off fluids. Primarily using flow cytofluorometry methodologies, into PS+ microparticles (114). Intriguingly, studies also shed platelet-derived microparticles have been observed in different 2 light on PS microparticles in body fluids (111, 115–117), inflammatory conditions in which platelets are activated (118, by guest on October 1, 2021. Copyright 2015 Pageant Media Ltd. http://classic.jimmunol.org Downloaded from

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 de- struction. (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 BRIEF REVIEWS: PLATELETS AND INFLAMMATION

119), and their levels often correlate with disease progression. highly regulated, because this is important to prevent serious For instance, levels of platelet-derived microparticles are in- bleeding when platelet counts are low, as well as to prevent creased in blood and synovial fluid of patients affected with vascular occlusion and organ damage when platelet counts are rheumatoid arthritis (RA), the most common autoimmune increased. Recently, it was elegantly shown that platelet pro- joint disorder (8, 120–123). Consistently, different groups duction can be regulated by binding of desialylated platelets to found that platelet depletion in a murine model of RA the hepatic Ashwell–Morell receptor, which induces expres- attenuates inflammation (8, 124). Although microparticles are sion of TPO in the liver via JAK2-STAT3 signaling (133). found in sterile, as well as in infectious, inflammatory dis- Acute bacterial or viral infections are known to potentiate orders, it is often not clear what platelet trigger is behind their ITP, an autoimmune bleeding disorder in which platelets are release. Multiple activation pathways might promote the targeted (134). The pathophysiological mechanism of acute generation of microparticles in inflammation, such as high infection–associated destruction of platelets is incompletely shear forces, platelet receptor activation, and apoptosis. In understood, but several likely scenarios have been suggested. RA, the activation of platelets through the collagen receptor One of them is molecular mimicry between viral/bacterial glycoprotein VI (GPVI) induces the formation of micro- Ags and platelet Ags, leading to the production of autoanti- particles, whereas in sepsis, microparticles can be produced via bodies that cross-react (135–139). Also, several patients with the stimulation of platelet TLR-4 by bacterial LPS (8, 125). Helicobacter pylori (Gram-negative bacterium)–related ITP Interestingly, the microparticles shed through both signals exhibited increased platelet count following H. pylori–eradi- (GPVI and TLR-4) are rich in IL-1, pointing to their role in cation therapy (140). In line with this, LPS, a Gram-negative amplification of inflammation (8, 125). Platelets also partic- bacterial endotoxin, enhanced FcgR-mediated phagocytosis ipate in adaptive immunity through stimulation of FcgRIIA. of anti-platelet Ab–opsonized platelets in vitro (37), as well Indeed, in immunized subjects, bacterial components and as a potent synergistic effect of anti-platelet Abs and LPS, well-conserved epitopes expressed by influenza viruses are resulting in platelet clearance in vivo (141). Therefore, LPS capable of forming immune complexes that activate FcgRIIA may be an important mediator of Ab-mediated platelet clear- (126, 127), leading to the formation of microparticles. ance during Gram-negative infections; despite not knowing Functionally, platelet microparticles (PMPs) are thought to the exact working mechanism, triggering of phagocyte and/or participate in cell–cell communication. The PMP cargo is vast platelet TLR4 could be relevant. Recently, C-reactive pro- and includes cytokines and chemokines (e.g., IL-1, RANTES), tein (CRP) was identified as a novel pathogenic serum factor potent lipid mediators (e.g., thromboxane A2), functional that enhances IgG-mediated platelet destruction in vitro and enzymes (e.g., inducible NO synthase), surface receptors (e.g., in vivo (142). CRP is an acute-phase protein, also present in CD40L), nucleic acids (e.g., microRNA), autoantigens (e.g., healthy individuals, which increases rapidly during acute in- citrullinated fibrinogen), transcription factors (e.g., PPARg, fections. CRP was found to be increased in children with ITP, RuvB-like2, STAT3, STAT5a), and even respiratory-compe- and treatment with IVIg was associated with increased platelet tent mitochondria, all of them potentially having an impact counts, decreased CRP levels, and reduced clinical bleeding by guest on October 1, 2021. Copyright 2015 Pageant Media Ltd. on the cell targeted by microparticles (103, 117–119, 128– severity (142). Moreover, elevated CRP at diagnosis corre- 130). Because they express surface receptors and PS (although sponded to slower platelet count recovery after 3 mo (142). 2 some are PS ), microparticles interact with other cells through The suggested mechanism of action was independent of integrin and via the PS-binding proteins lactaderhin (131) platelet FcgRIIA but based on platelet oxidation (triggered and developmental endothelial locus-1 (Del-1) (132). Hence, by anti-platelet Abs and the phagocyte NADPH oxidase sys- 2 2 2 2 lactaderhin / and Del-1 / mice express higher levels of tem), which resulted in exposure of platelet phosphorylcho- plasma microparticles compared with their wild-type counter- line residues to which CRP could bind and, thereby, enhance parts, suggesting that these proteins are involved in micro- IgG-mediated platelet phagocytosis via interaction with phago- http://classic.jimmunol.org particle clearance and in microparticle interaction with other cytic FcRs (142). Therefore, CRP could be an important fac- cells (131, 132). Transcription factors packaged inside PMPs tor in Ab-mediated platelet destruction in bacterial (Gram- can enable transcellular effects, such as PPARg, which was negative and/or Gram-positive) or viral infections associated shown to be transported into PMPs and transferred to mono- with ITP. cytes where it elicited transcellular effects (129). However, it is A summary of all the above-mentioned characteristics is unknown whether specific internalization signals exist beyond shown in Table I and illustrated in Fig. 1.

Downloaded from the initial contact of microparticles with the cellular recipient. Thus, microparticles can contribute to the dissemination of Conclusions inflammatory signals derived from platelets. Furthermore, given Platelets are best known as primary mediators of hemostasis that they are induced in several inflammatory pathologies, and thrombin generation; however, like leukocytes, they have microparticles appear to be potent biomarkers. Understanding multiple functions related to inflammation/immunity. It ap- the molecular mechanisms implicated in microparticle functions pears that these anucleate cellular fragments express and secrete and improvements in their assessment will contribute to the several diverse pro- and anti-inflammatory molecules that serve delineation of their physio(patho)logical roles. to initiate and modulate immune functions. These aspects of platelets and immunity have initiated a new understanding of Infections and thrombocytopenia the role of platelets in infectious processes and how they can In addition to being suppressed by platelets, acute viral or significantly modulate the immune system. bacterial infections can often lead to low platelet counts or thrombocytopenia, which might be a viral or bacterial strategy Disclosures to evade immune responses. The production of platelets is The authors have no financial conflicts of interest. The Journal of Immunology 5585

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