Platelets as Immune Cells in Infectious Diseases

Cornelia Speth; Jürgen Löffler; Sven Krappmann; Cornelia Lass-Flörl; Günter Rambach


Future Microbiol. 2013;8(11):1431-1451. 

In This Article

Immunocompetence of Platelets

Despite being acaryote cell fragments, platelets share a number of properties of host defense with their big nucleated relatives and represent important elements in innate immunity. For these purposes, they have developed a number of physiological skills (Box 1 & Figure 1). They sense pathogens by various surface receptors, attach to them and become activated, thereby releasing the content of their granules. Consequently, antimicrobial peptides exert direct effects against pathogens, and a number of cytokines/chemokines attract and activate other immune cells. Endocytosis of pathogens, production of reactive oxygen species (ROS) and various interactions with the complement system and cells of the innate and adaptive immune systems could be shown, as described in the following sections. All these mechanisms support the fight against infections, but can also harbor deleterious sequelae such as thrombosis and exceeding inflammatory reactions. Since platelets can be described as immune cells with a broad range of antimicrobial functions, it is difficult to decide which function or aspect is the most relevant for the clinical outcome. To answer this, additional studies are necessary in the future.

Figure 1.

Antimicrobial capacities and effector mechanisms that can be exerted by platelets in the course of infections.
Platelets (in red) have various functions that target the different pathogens; however, they also modulate the extent of inflammation and interact with other immune cells of innate and adaptive immunity. Further details are found in the text. See Box 1 for labeling of exerted functions.
AMP: Antimicrobial peptide.

Platelet Receptors to Recognize Pathogens &/or Pathogen-induced Inflammation

A variety of surface receptors enable platelets to sense the presence of invading pathogens or induced inflammation (Box 1). GPIIb/IIIa (α2bβ3 integrin) is platelet-specific and the most abundant receptor on the plasma membrane;[22] its ligands fibrinogen and fibronectin can, when bound to the pathogen surface, act as bridging proteins, mediating adhesion of microbes to GPIIb/IIIa on platelets and subsequent activation.[23] Direct binding of GPIIb/IIIa to bacteria and viruses is also possible.[24–26]

GPIbα is another surface receptor exclusively expressed on platelets and megakaryocytes, and can attach to bacteria either directly or with vWF as a bridging molecule;[27] however, not all of these binding reactions result in platelet activation.[23] The platelet glycoproteins GPIa/IIa (α2β1 integrin) and GPVI (a member of the Ig superfamily and primary signaling receptor for platelet activation by collagen) are also capable of binding viruses.[25,28]

Platelets express the Fc receptor FcγRIIa, which binds to IgG in immune complexes with all pathogens. It plays an important role in pathogen-induced aggregation and/or activation of platelets and can also enhance interactions mediated by GPIIb/IIIa and GPIbα.[23,29]

Toll-like receptors (TLRs) are a family of receptors that play a key role for sensing conserved pathogen-associated molecular patterns.[30] Platelets were shown to express TLR1–9 to respond to a broad range of foreign molecules.[1,31] Platelet activation, release of immunomodulatory agents, activations of other cells and presentation of pathogens for phagocytosis are mediated by TLRs.[1,32,33] For example, TLR2 recognizes a variety of bacterial structures such as lipoproteins, lipoteichoic acid and peptidoglycan, but also viral structural proteins and fungal β-glucan and mannan.[33] TLR4 is another central receptor on platelets that mediates recognition of bacteria, but also interaction with and activation of neutrophils.[1] A newly discovered electron-dense tubular system-related compartment, called T granule, has been shown to harbor TLR9 in particular, which acts as a receptor for unmethylated CpG islands found in bacterial and viral DNA.[34]

The complement system, triggered by different pathways, implements multiple functions, including direct and indirect antimicrobial host defense (e.g., cell lysis, opsonization and chemotaxis).[35] The reciprocal activation of complement and platelets guarantees an optimal immune network.[36,37] Stimulated platelets and platelet microparticles could be demonstrated to mediate complement activation by exposure of P-selectin (CD62P), complement receptor gC1qR or chondroitine sulphate.[36,38,39] Furthermore, the expression of complement receptors CR2, CR3, CR4, C3aR, C5aR, gC1qR and cC1qR were shown on platelets.[40–46] However, the precise functions of complement–platelet interactions in host defense and inflammatory processes remain to be urgently clarified.[23,25,38]

A range of cytokine/chemokine receptors on platelets can sense the pathogen-induced inflammatory reaction and induce activation, aggregation and release of granule contents.[11,47]

Platelet Microbicidal Peptides

Antimicrobial peptides are small, cationic, amphipathic polypeptides that mainly target microbial cell membranes, but may also affect intracellular molecules or cell walls of microbes.[48,49] Platelets store a variety of platelet microbicidal peptides (PMPs), also called thrombocidins, in their α-granules. They are released during platelet activation[11,50] and can kill a range of bacteria, fungi and viruses.[51] Several PMPs are related to the CXC and CC chemokine families; these peptides are termed kinocidins.[50,51] For example, platelet factor-4 (PF-4; CXCL4), PBP and NAP-2 are members of the CXC chemokines,[50,52] while RANTES and MIP-3a belong to the CC family.[48] More detailed overviews are given in.[11,48,50] Kinocidins indeed show both microbicidal activity and properties of classical chemokines, such as attraction and activation of phagocytes and lymphocytes.[11,50] Recently, extragranular occurrence of β-defensin 1 was detected in platelets, which exerts potent antimicrobial properties.[53] This multitude of PMPs generated by platelets underlines their role as important antimicrobial players. The storage both in granules and in the cytoplasm guarantees that PMPs are released both by pathogen-induced platelet activation and by pathogen-induced platelet damage (see 'Platelet microbicidal peptides' section).

Production of ROS

Platelets are known to generate ROS (superoxide, peroxide and hydroxyl radicals) upon activation. Various activators, including microbial products such as lipopolysaccharide, can induce ROS generation, and TLR-2 and ITAM receptors were shown to be involved in this process.[54–56] Release of ROS might be associated with thrombus formation. However, the relevance of the secreted radicals for antimicrobial defense is discussed controversially.[57,58]

Phagocytotic Activity of Platelets

Platelets were shown to endocytose latex particles, FcγRIIa-bound IgG immune complexes and pathogens including Staphylococcus aureus and HIV.[25,59–63] By this mechanism, platelets can serve to remove IgG complexes from the circulation.[61,64] Internalization of pathogens may cause their destruction, but alternatively enable their survival and prolonged transport in the host.[62]

Interaction With Other Immune Cells & Modulation of Inflammation

Platelets are involved in a multitude of intercellular communications that contribute to host defense, in addition to inflammation, thrombosis and atherosclerosis.[65] Upon activation, platelets release a range of chemokines that attract and activate leukocytes (overview and effects in[18,66,67]); concurrently, various surface molecules (P-selectin, JAM-3, TLRs, GPIIb/IIIa and CD40L [CD154]), the proinflammatory cytokine IL-1 and growth factors (PDGF and TGF-β) mediate the crosstalk with endothelial cells and leukocytes[1,68] to activate them and facilitate transendothelial migration at sites of injury or inflammation.[9,68–72] Microparticles, budded from activated platelets, show a similar surface molecule pattern. They activate leukocytes and endothelial cells and appear to play an important role in a variety of inflammatory diseases.[73–75]

Platelets induce a multitude of effects in their target cells thus bridging innate and adaptive immunity. P-selectin-mediated adhesion to neutrophils can induce degranulation of azurophilic granules and the release of antimicrobial defensins and lysozymes.[71,76,77] Interactions of platelets with neutrophils could be demonstrated to amplify the bacteria-induced respiratory burst and to enhance phagocytosis of bacteria.[78,79] Furthermore, platelets can support the formation of neutrophil extracellular traps (NETs).[32,53] Platelets bind or internalize IgG immune complexes and are subsequently internalized by neutrophils and monocytes, thereby contributing to clearance of such complexes from the circulation.[64] Monocyte attraction, activation, adhesion to endothelium, transmigration and differentiation to macrophages or dendritic cells are mediated by activated platelets;[9,66,80–83] additionally, they induce the secretion of proinflammatory cytokines in macrophages.[84] Induction of activation and maturation of dendritic cells by platelets was demonstrated by several groups.[21,85–87]

Via CD40L binding to CD40 on B cells, platelets were shown to trigger B-cell proliferation, differentiation, isotype switching and memory B-cell generation.[75,88–90]

T-cell costimulatory and adhesion molecules, including CD40, CD44, ICAM-2 and DC-SIGN, are present on platelets. Recently, antigen processing and presentation by MHC I, as well as direct activation of naive T cells were shown.[91] The effects of platelets on T cells are mediated via various chemokines or by direct contact and include T-cell differentiation, activation and induction of cytokine production by T cells; furthermore, germinal center formation is supported.[75,91–93] This multitude of interactions with lymphocytes indicates that platelets are essential promoters of the adaptive immunity.