Th eJournal of Brief Reviews Immunology Nouvelle Cuisine: Platelets 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 platelet’s ability to aggregate and activate the becoming increasingly clear that platelets have an in- coagulation 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 cytokines and chemokines, 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 megakaryocytes 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 megakaryocyte 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 monocytes 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 protein; 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, glycoprotein VI; ITP, immune thrombocy- Canada; Department of Pharmacology, University of Toronto, Toronto, Ontario M5B { topenia; NET, neutrophil 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, thrombopoietin. Received for publication February 3, 2015. Accepted for publication March 26, 2015. Ó 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 INFLAMMATION 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). neutrophils, macrophages, and dendritic cells (DCs) (2, 32, Interestingly, platelets also were shown to be involved in the 33). TLRs are germline-encoded proteins 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 Plasmodium 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