Trends in Immunology
Platelets: signaling cells in the immune continuum
Section snippets
Platelets are rapidly targeted to sites of injury and infection
Because of their rapid accumulation and functional repertoire, platelets can have early roles in surveillance and information transfer similar to those accomplished by mast cells, macrophages and dendritic cells (DCs), which are pre-stationed in tissues to detect microbial invasion and wounding and provide advanced molecular intelligence and directives for subsequent responses [8]. Platelets undergo rapid homotypic aggregation in the blood (Figure 1) and adhesion to exposed subendothelial
The platelet secretome: activated platelets release inflammatory and immune-modulating factors
Activated platelets release factors of several classes that act as signals for target cells, including cells of the innate and adaptive immune systems (Table 1) 3, 4, 12, 13, 14, 15, 16, 17. Many secreted platelet factors are proteins and polypeptides that are stored in processed or precursor forms and can be rapidly released 12, 13, 14, 15, whereas others are the products of synthetic pathways that are rapidly triggered when platelets themselves receive activating signals (see later). The
Close encounters: platelet surface factors mediate intercellular signaling
Platelets not only secrete chemokines and other factors but also use signaling molecules anchored on the plasma membrane to mediate cell–cell adhesion and activate target cells (Figure 2). This provides a mechanism for spatially localized information transfer that is even more precise than paracrine secretion [6]. P-selectin, which is preformed and translocated from α granules to the surfaces of activated platelets, mediates adhesion to PMNs and monocytes by binding to a ligand on their plasma
Newly recognized synthetic capacities of activated platelets
Activated platelets rapidly produce thromboxane A2 (TXA2) (Table 1), a prothrombotic eicosanoid, from arachidonic acid in an enzymatic reaction catalyzed by constitutive cyclooxygenase-1 (COX-1). This pathway is a major therapeutic target in atherosclerotic vascular diseases [36]. Adherent platelets also synthesize PAF and use it to trigger local activation and adhesion of target leukocytes [6] (Figure 2). These examples illustrate the well known ability of activated platelets to synthesize
Cell–cell interactions involving platelets
The previous sections document that activated platelets release preformed mediators, display on their surfaces key members of ligand pairs, and synthesize new factors of several biochemical classes that can initiate, amplify or modify the immune continuum 7, 8 at multiple checkpoints and subserve defensive and surveillance functions. Cell–cell interactions involving platelets thus have the potential to exert crucial influences on inflammatory and immune outcomes. Platelet–platelet aggregation (
Platelet–DC interactions: information transfer to command and control adaptive immune cells
DCs link innate defensive responses and adaptive immunity 51, 56, 57. CD40L and IL-1β, which are displayed and released by platelets (see earlier), are among the most important endogenous ‘danger signals’ for DCs, and it has been suggested that platelets are early effectors of DC activation in tissue injury [57]. Murine platelets stimulated with thrombin induce in vitro activation and maturation of primary mouse bone marrow DCs by a mechanism dependent on platelet CD40L [31], consistent with
Platelets contribute to delayed hypersensitivity and adaptive immunity in vivo
Animal models support modulation of T-cell-mediated immune responses by platelets, including delayed-type hypersensitivity, contact sensitivity and adaptive immune responses to infection. As previously outlined, intravascular activated platelets reconstitute lymphocyte homing and responses to cutaneous antigen presentation in L-selectin-deficient mice, indicating crucial influences on lymphocyte trafficking and immunological memory in this model [28]. Circulating platelets also contribute
Concluding remarks
It is clear that platelets have signaling mechanisms and participate in cell–cell interactions that extend far beyond their traditional roles in haemostasis. Studies outlined in this Review indicate that these activities include interactions with key cells in the continuum of innate and adaptive immunity and that platelets might provide crucial signals in complex adaptive immune responses, establishing previously unrecognized sentinel and regulatory roles in tissue damage and infection.
Acknowledgements
We thank Thomas M. McIntyre and Stephan Lindemann for their collaboration, contributions, and insight into topics addressed in this review. We also thank many other collaborators and the fellows and students in our laboratories for their contributions, our technical staff for support of work cited, and our administrative staff. Diana Lim drafted the artwork and Michele Czerwinski and Mary Madsen prepared the manuscript. We also acknowledge the contributions of funding agencies that have
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