Platelets have long been known for their role in hemostasis. In this, platelet adhesion and activation leads to the formation of a firm thrombus and thus the sealing of a damaged blood vessel. More recently, inflammatory modes of function have been attributed to these non–nuclei-containing cellular fragments. Interaction with leukocytes, secretion of proinflammatory mediators, and migratory behavior are some of the recent discoveries. Nonetheless, platelets also have anti-inflammatory potential by regulating macrophage functions, regulatory T cells, and secretion of proresolving mediators. This review summarizes current knowledge of platelet functions with a special focus on inflammation and resolution of inflammation.

Organism homeostasis has to be guaranteed at all times by providing specific security measures. The hematopoietic system contains cellular populations that exhibit immune defense and hemostatic functions, sealing vascular damage and combating invasion of pathogens. The role of platelets in hemostasis is well established, and these cells are the first responders in hemostatic clot formation, involving the adhesion and activation of platelets at a site of vascular injury. Nevertheless, these small cellular fragments have been shown to feature a much wider variety of functions than previously recognized (Fig. 1).

FIGURE 1.

The destiny of a platelet in inflammation and resolution. Bacterial invasion results in the recruitment and activation of immune cells, including platelets. Equally, a vascular injury results in platelet activation and depending on the site and sort of injury (e.g., endothelial denudation versus atherosclerotic plaque formation), an inflammatory interplay. An evolving thrombus as well as recruited destructive/harmful immune cells (e.g., neutrophils) need to be removed, and the executed inflammatory or hemostatic reaction has to be stopped and resolved for tissue homeostasis and unimpaired blood flow. Platelets contribute to the resolution of inflammation by a multitude of factors, including interaction and modification of T cells and macrophages. Platelet production and sequestration are equally affected by inflammatory processes.

FIGURE 1.

The destiny of a platelet in inflammation and resolution. Bacterial invasion results in the recruitment and activation of immune cells, including platelets. Equally, a vascular injury results in platelet activation and depending on the site and sort of injury (e.g., endothelial denudation versus atherosclerotic plaque formation), an inflammatory interplay. An evolving thrombus as well as recruited destructive/harmful immune cells (e.g., neutrophils) need to be removed, and the executed inflammatory or hemostatic reaction has to be stopped and resolved for tissue homeostasis and unimpaired blood flow. Platelets contribute to the resolution of inflammation by a multitude of factors, including interaction and modification of T cells and macrophages. Platelet production and sequestration are equally affected by inflammatory processes.

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Platelets are small (mean platelet volume: ∼8.9 fl in humans, 4.3 fl in mice) anucleate fragments that are derived from megakaryocytes (1, 2). They were first described by Schultze in 1865 and subsequently by Bizzozero in 1882 (3). Humans contain ∼150 to 400 × 109 platelets per liter, whereas mice contain drastically higher amounts of platelets (∼1000 × 109 platelets per liter), which has to be taken into consideration when interpreting data from animal models (46). Platelet production occurs within the bone marrow, and recent data suggest that megakaryocytic cells and platelet production can also be observed in the lung (7). Platelets arise from megakaryocytes, and their production (thrombopoiesis) is regulated among others by thrombopoietin (THPO) (8, 9). Regulation of platelet counts relies on a delicate feedback mechanism in which binding of THPO to its receptor on both platelets and megakaryocytes leads to reduced plasma levels, whereas a reduction in systemic platelet counts results in reduced scavenging of THPO and thus increased plasma values. Platelet numbers are affected by a variety of factors, such as inherent disease phenotypes or inflammatory complications. It has been shown that sepsis might impact platelet numbers (10), and a reduction in the number of platelets during sepsis is associated with a worse outcome (11). This observation might be caused by the fact that an increased inflammatory response induces more platelet adhesion in the microcirculation (12). Interestingly, also other factors, such as age (1315), gender (16, 17), and circadian rhythms (18, 19), are known to affect platelet numbers and functions.

Platelets circulate within the blood stream, executing their functions, and they can be removed in the spleen (Ab-mediated) and liver (desialylation dependent, Fc-independent) or, under certain conditions, also in lung and brain and can be phagocytosed in a vWF-dependent manner by macrophages (2025).

Following an endothelial injury, platelets adhere to the subendothelial layer, are activated, aggregate, and ultimately form a firm thrombus, occluding the injured site to prevent leakage of intravascular blood into the extravasal compartment, thus executing barrier functions. Each step relies on specific surface receptors. Adhesion under high shear is mainly mediated by the binding of GpIb/V/IX on platelets to collagen-bound vWF, thereby facilitating the interaction of GpVI with collagen. This GpVI–collagen interaction can then result in platelet activation (26). Interestingly, GpVI is also capable of binding to fibrin, leading to further GpVI-mediated platelet activation and thrombus stabilization (27). Platelets can furthermore adhere to collagen via GpIa/IIa (28), and GpIIb/IIIa is also capable of binding to vWF (29, 30). Binding of activators (e.g., thrombin to GpIb/V/IX and PARs, collagen to GpVI, ADP to P2Y receptors, thromboxane A2 to thromboxane receptor) leads to intracellular signaling events and a shape change of the formerly discoid platelets into an either fried-egg (lamellipodia) or star-like shape (filopodia) (3133). Activation of platelets also induces a conformational change of the GpIIb/IIIa integrin to a high affinity conformation, production of thromboxane A2, and mobilization and release of intracellular granules (α- and dense granules) which contain secondary mediators, including vWF, ADP, calcium, epinephrine, histamine, RANTES/CCL5, Pf4/CXCL4, and serotonin (34).

Immunothrombosis.

Platelets are functionally multifaceted cells (Fig. 1), capable of interacting with various cell types, including leukocytes. Interactions of platelets with leukocytes have been observed in both hemostasis and immune defense, resulting in the creation of the term “immunothrombosis” (Fig. 2). This term exemplifies the interaction of platelets with other immune cells, as well as plasmatic coagulation components, resulting in thrombus formation, possibly to protect the host organism and restrict the infection to the local environment, as has been nicely summarized by Gaertner and Massberg (35). This concept was recently challenged; in a model of Salmonella Typhimurium infection, formed thrombi contained only limited amounts of bacteria in vivo, contradicting the notion of a thrombus as a major bacterial-capturing site throughout the whole body (36, 37). Rather, an organ or pathogen specificity was detected in the formation of thrombi in this study (37).

FIGURE 2.

Platelet receptors from hemostasis to resolution. Platelets participate in various tasks within the organism, including hemostasis, immunothrombosis, inflammation, and resolution of inflammation. Platelet receptors appear to contribute to not just one singular process but rather a multitude of overlapping and not clearly separable processes. This image contains selected receptors.

FIGURE 2.

Platelet receptors from hemostasis to resolution. Platelets participate in various tasks within the organism, including hemostasis, immunothrombosis, inflammation, and resolution of inflammation. Platelet receptors appear to contribute to not just one singular process but rather a multitude of overlapping and not clearly separable processes. This image contains selected receptors.

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Mechanisms of platelet–leukocyte interaction.

The interaction of platelets with leukocytes is of utmost relevance in the regulation of both inflammatory and hemostatic processes. After activation, platelets express P-selectin on their cell surface, which can interact with the selectin receptor PSGL-1 expressed on leukocytes. In an inflammatory setting, platelets influence leukocyte emigration by capturing leukocytes at specific extravasation sites, thus facilitating tissue infiltration in a PSGL-1/P-selectin–dependent manner, somewhat paving the path to extravasation (38). Indeed, neutrophils actively search for activated platelets to engage in a PSGL-1–mediated signaling event (39). Similarly, also in a sterile liver injury model, platelets provide a route for neutrophil extravasation in a GpIIb/IIIa dependent manner (40).

Platelets may also interact with other cells (including adjacent platelets, leukocytes, and endothelial cells) not only via direct receptor-mediated cell–cell interaction but also by binding to fibrinogen via GpIIb/IIIa (Fig. 2). Activated platelets, expressing the high affinity conformation of the GpIIb/IIIa integrin receptor, are capable of binding to fibrinogen, leading to crosslinking with neutrophils via their surface integrin receptor Mac-1 (41). The leukocyte integrin Mac-1 can also directly interact with the platelet receptor GpIbα and thus influence thrombosis (42). Such platelet–leukocyte interaction can be observed in venous thrombosis, implicating a leukocyte-rich thrombus formation and showing the interaction of the hemostatic system with the immune system. Indeed, venous thrombosis depends on the interplay of monocytes, platelets, plasmatic coagulation, and neutrophils (43).

Platelet–monocyte interaction.

Platelet–monocyte interactions are not only important in venous thrombosis. In rheumatoid arthritis, platelet–monocyte complex formation is increased and platelets can induce a proinflammatory phenotype in monocytes in a CD147, PSGL-1, EP1/EP2, and COX-2–dependent manner (4446). This interaction also assists in the adhesion of monocytes to the endothelium (47) and even an upregulation and activation of β1 and β2 integrins on monocytes, thus supporting proinflammatory recruitment of monocytes (48).

Notwithstanding, platelets when opsonized with IgG and interacting with monocytes are also capable of promoting a phenotype change toward IL-10–producing regulatory monocytes, emphasizing the bipolar character of platelets in the propagation of inflammation on one hand, but also control and resolution of inflammation on the other (49).

Platelet–leukocyte interplay in infection.

During pulmonary infection, platelets regulate ICAM-1 expression on endothelial cells via a shuttling process in which the PSGL-1/P-selectin–mediated platelet–neutrophil aggregate formation evolves in GpIb–Mac1-induced extracellular vesicle–mediated shuttling of arachidonic acid from neutrophils to platelets. This induces platelet thromboxane synthesis, and the thromboxane subsequently leads to the upregulation of endothelial ICAM-1 (50). This process is needed for neutrophils to competently penetrate an organ, the lung in this study, and combat invading pathogens. Indeed, leukocyte infiltration, bacterial burden and survival in a model of Escherichia coli induced pneumonia are platelet dependent (50). Comparable results were obtained in a model of GpVI-deficient mice in Klebsiella pneumoniae–induced pulmonary inflammation (51). Additionally, during bacterial infection, antimicrobial peptides, such as LL-37/CRAMP, are released from activated platelets. LL-37 may preactivate platelets and facilitate not only thrombus formation but also platelet–leukocyte complex formation (52, 53).

Interestingly, the formation of platelet–neutrophil complexes in the lung depends critically on platelet expressed inositol hexakisphosphate kinase 1 (IP6k1) (54). In addition, CD40L expressed on platelets is a key regulator of platelet–leukocyte complex formation and influences regulatory T cell recruitment in atherosclerosis (55). Not only in the lung, but also in the kidney, is platelet–leukocyte interplay of utmost relevance, as platelet P-selectin is needed for competent infiltration of leukocytes into outer and inner medulla of the kidney in an ischemia-reperfusion injury model (56). A codependence on platelets and neutrophils in bacterial infection has also been observed in the liver, in which platelets migrate in order to collect bacteria and present it to neutrophils for subsequent phagocytosis (57). Neutrophils are capable of releasing neutrophil extracellular traps (NETs). In the setting of a bacterial infection, these NETs may capture and kill bacteria (58). The platelet–bacteria interaction in lung and liver indeed depends on TLR4 and results in formation of NETs (59). Even though the platelet–NETosis axis appears to be helpful in bacterial capturing, it may subsequently induce thrombin activation and intravascular coagulation in sepsis, possibly leading to multiorgan failure (60).

Platelet–leukocyte complexes and NETs in sterile inflammation.

Another clinically relevant immune complication relying on NET formation and often appearing in an inflammatory context is heparin induced thrombocytopenia. This platelet factor 4 (Pf4)–dependent pathologic condition results in platelet–neutrophil aggregation, formation of thrombi, and a reduction in platelet numbers. The formation of thrombi could be blocked by inhibiting of NET formation, whereas thrombocytopenia was unaffected by this, emphasizing the complexity of platelet–neutrophil interplay (61).

Leukocyte activation by secreted mediators.

Aside from direct receptor-mediated interactions as mentioned above, platelets are capable of activating leukocytes via secreted mediators, such as C-X-C-motif chemokines or the damage-associated molecular pattern HMGB-1. Platelet-derived HMGB-1 results in NETosis, induces monocyte accumulation, influences thrombotic diseases (6264), and mediates bacterial clearance in a cecal ligation and puncture model (65). Intriguingly, activated platelets themselves can bind HMGB-1 on their surface via the receptor of advanced glycation endproducts (RAGE) and TLR-4, and HMGB-1 is capable of enhancing the activation of platelets without directly activating the platelets on its own (66).

Termination of inflammation.

With regard to the termination of the inflammatory process, in vitro data suggest a platelet-mediated delay of human neutrophil apoptosis (67). Platelet Pf4 diminishes neutrophil apoptosis in a model of arterial occlusion (68), and leukocyte apoptosis is associated with increased presence of platelet–leukocyte complexes (69).

Role of THPO.

Inflammation impacts platelet consumption, function, and production (70). Sepsis is associated with thrombocytopenia and changes in THPO levels (10). At the same time, thrombocytopenia on admission is associated with increased mortality in septic intensive care unit patients (71). THPO is known to activate platelets, induce formation of platelet–leukocyte aggregates, and increase the fMLP-mediated reactive oxygen species release of neutrophils (72, 73). Blocking of THPO leads to a reduction in organ damage in experimental sepsis (74), exemplifying that a loss of platelets, which is associated with increased THPO levels, is directly linked to outcome and organ protection in inflammation.

Platelet activity in sepsis.

Aside from platelet numbers and its consequences on THPO levels, platelet activity is also affected throughout the course of inflammation. Although spontaneous platelet activity could be observed in severely septic patients, stimulus-dependent ex vivo aggregation of these platelets was significantly reduced (75). The dysfunctional aggregation of these platelets correlates with the severity of sepsis, and interestingly, a reduction in PAC-1 binding, detecting the high affinity conformation of GpIIb/IIIa, was observed in one study, even though a possible baseline difference that might be in line with a preactivation of these platelets was not reported (76). Indeed, another study showed that sepsis occurrence correlates with the fibrinogen-binding response of isolated platelets from patients, exemplifying an increased fibrinogen binding of circulating platelets in patients with risk for sepsis (77). Even though conflicting data exists with regard to platelet aggregation, overall, clinical data demonstrate a hyperreactive phenotype of platelets in septic patients (78, 79). Also, an animal study using a septic mouse model suggested a prothrombotic, hyperreactive phenotype of platelets with the occurrence of platelet-rich thrombi and organ damage. Increased P-selectin exposure and fibrinogen binding as well as platelet–leukocyte complex formation appear in this model within the first 24–48 h. Also, animals following cecal ligation and puncture showed an increased thrombus formation rate compared with sham mice (12).

Platelet–bacteria interaction.

During bacterial infection, platelets may interact directly with bacteria via binding of different bacterial components to multiple receptors on platelets, including TLR-4, FcγRIIa, GpIIb/IIIa, and other receptors (80). This interaction evokes, on one hand, an activation response and platelet aggregation (81); on the other hand it leads to bacterial capturing, bundling, and migration of platelets (57). Consequently, inflammatory cells are attracted and platelets assist in bacterial clearance by presenting bacteria to neutrophils for inducing phagocytic elimination. Interestingly, bacteria caught by Kupffer cells in the liver are enclosed by platelets that are recruited in a GpIb, vWF, and GpIIb-dependent manner, impacting bacterial clearance and host survival (82). Platelets are additionally capable of releasing antimicrobial molecules themselves, such as the aforementioned LL37 (53), thus impacting host defense. Of note, platelets can directly kill Pf4-opsonized Gram-negative bacteria, such as E. coli (83). Microbicidal properties of Pf4 are also visible in Plasmodium falciparum infection, in which Pf4 lyses the digestive vacuole of the parasite inside of infected erythrocytes (84, 85).

Viral infections and inflammasome.

Aside from direct bactericidal properties, macrophage phagocytosis is enhanced by platelets, not via direct interaction but through IL-1β (86). For further immune-defense–related activity, platelets express MHC class I and are capable of antigenic protein uptake, Ag-presentation, and coactivation of T cells (87). In viral infections, such as influenza infection, platelets engulf viral particles and release complement factor 3, which ultimately results in neutrophil aggregation and neutrophil DNA release, leading to host defense but also possible microthrombotic complications (88). Viral infections, more specifically dengue and influenza virus infections, also lead to the upregulation of IFITM3 in human platelets and megakaryocytes, and IFITM3 in megakaryocytes mediates the secretion of antiviral proteins, thus restricting dengue virus infection (89).

Following dengue infection, the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is assembled, resulting in increased release of IL-1β, which subsequently augments vascular permeability in dengue-infected subjects (90). Activation of platelet NLRP3 has also been observed in cecal ligation and puncture–mediated sepsis, showing increased levels of IL-1β as well as IL-18 in lungs and kidneys of septic rats (91). NLRP3 is further implicated in the activation of platelets and in vitro thrombus formation together with BTK (92), and it has been shown to affect the GpIIb/IIIa outside–in signaling response (93). Nonetheless, it is worth noting that the inflammasome-related IL-1 cytokine release by platelets is under debate, as it has been suggested that for example leukocyte contamination can lead to false positive results (94, 95).

Platelets in sterile inflammation.

Aside from pathogen-related inflammation, platelets are also of relevance in sterile inflammation. With regard to the aforementioned NLRP3 inflammasome, an upregulation of platelet NLRP3 could be observed in a model of hindlimb ischemia in a TLR4-dependent manner, ultimately triggering platelet aggregation (96). In another sterile inflammatory condition, in nonalcoholic steatohepatitis, platelet-dependent liver damage was observed (97). Mechanistically, the authors showed that platelet GpIbα, α-granule release, and hyaluronan–CD44-mediated interaction with Kupffer cells is needed for development of nonalcoholic steatohepatitis and subsequent hepatocellular carcinoma. In addition, another study investigating a model of experimental autoimmune encephalomyelitis showed the importance of platelet GpIbα for pathogenesis of experimental autoimmune encephalomyelitis by influencing leukocyte CNS infiltration. Thus, it appears that as a general mechanism, GpIbα serves as an “inflammatory” receptor, playing an important role for organ damage during sterile inflammation (98).

Fascinatingly, this same receptor might not solely serve as an inflammatory receptor by, for example, impacting the formation of platelet–leukocyte aggregates, but it appears to also be responsible for the suppression of TNF-α secretion from monocytes and inhibition of Mac-1 upregulation on neutrophils at later time points (24 h), possibly coinciding with the onset of a resolution phase in systemic inflammation (99). Also, in immune-complex–mediated inflammation, platelets on one hand assist in neutrophil activation, leading to organ invasion and damage, and on the other hand, in sharp contrast, show protective effects in that they seal extravasation sites of leukocytes and thus help in restoration of vascular integrity and barrier function, protecting against bleeding complications and exemplifying a “bipolar” character of platelets throughout inflammation (100). However, platelets also contribute to the inflammatory response of other nonbacterial diseases. In allergic inflammation, platelets are involved in the pathophysiology of the disease and can be found in lung tissue (101). The relocation of platelets into the lung suggests that allergens may, to some extent, induce migration of platelets (102). Such relocation of platelets is likely to affect overall blood-inherent platelet numbers and thus possibly THPO levels. Of note, in a smaller study investigating allergic asthma patients it was shown that these patients have a higher platelet count (103), once again linking platelet production to inflammation. However, another group reported a decreased mean platelet volume but no clear correlation with platelet numbers (104). Fascinatingly, platelets themselves even promote allergic asthma progression in a CD40L-dependent manner, inhibiting regulatory T cells and supporting (proallergic) Th2 responses (105). Also, platelet exocytosis, mediated by Munc13-4, was recently associated with the development of allergic airway inflammation (106), and platelets expressing the FcγRIIa even mediate anaphylaxis, the most severe allergic complication (107). It was observed that platelets from allergic patients show an activated phenotype, visible by increased plasma levels of Pf4 in asthma patients, increased platelet–eosinophil complex formation, serotonin release, and higher soluble P-selectin levels (108111). Nonetheless, this platelet phenotype leaves the patients with slight hemostatic defects, resulting in prolonged bleeding time and reduced collagen- and ADP-dependent platelet aggregation (112). This exemplifies either a contradictory inflammatory/hemostatic platelet environment in which platelets are inflammatory active but hemostatically impaired or possibly a state of hemostatic exhaustion due to the chronic activation of platelets (101).

Platelet-derived extracellular vesicles in immune regulation.

Platelets are capable of releasing shedding-related membrane microvesicles (spontaneous releasates termed ectosomes) and exocytosis-related vesicles of smaller magnitude, exosomes (113). Platelet microvesicles exhibit surface molecules related to platelets, such as GpIb or GpIIb/IIIa, and thus can interact with a multitude of cells. Within leukocytes, platelet-derived extracellular vesicles preferentially interact with granulocytes and monocytes, mostly CD14++CD16+ monocytes in whole blood (114). Platelet-derived microvesicles can capture and activate circulating neutrophils and facilitate neutrophil–endothelial cell interactions, thus acting in a proinflammatory manner (115). Also, these microvesicles are described to deposit RANTES on activated endothelial cells which—again in a proinflammatory manner—subsequently attracts monocytes (116). Furthermore, these small vesicles bind to smooth muscle cells, which leads to increased SMC migration, proliferation, and monocyte adhesion to vesicle-treated smooth muscle cells (117). In contrast, in an anti-inflammatory mode of function, microvesicles can also induce the differentiation of naive CD4+ T cells into regulatory T cells (118) and affect macrophage phenotypes (reduced TNF-α and IL-10 release by activated macrophages, induction of TGF-β release) and also impact differentiation of monocytes to immature dendritic cells, for example leading to reduced phagocytic activity (119). The smaller exosomes also contain micro RNAs that regulate endothelial cell signaling pathways, such as Wnt signaling (120), with Wnt/β-catenin signaling being known for reducing immune cell infiltration in a model of experimental autoimmune encephalomyelitis (121).

Platelet–endothelial cell interactions.

Inflammation leads to activation of endothelial cells. Platelets are known to roll on activated endothelial cells in a P-selectin/GpIb-dependent manner (122125), whereas the expression and thus contribution of PSGL-1 on platelets to platelet–endothelial interactions has been critically discussed (126, 127). Interaction of platelets with injured endothelial cells is additionally mediated by PECAM-1 (128130). The main effects of such interaction appear to be, on one hand, the regulation of endothelial barrier and leakage as described above, whereas on the other hand, presence of platelets on endothelial cells facilitates capturing and subsequent tissue infiltration of inflammatory cells.

Platelets and the complement system.

Platelets do also interact with the complement system. The complement system relies on three activation cascades, namely the classical (activated by Ag-complexed IgM or IgG molecules binding to C1), alternative (by spontaneous low-level hydrolysis of C3), and lectin pathway (pathogen-associated-molecular pattern–lectin-pathway recognition molecule binding). Platelets contain multiple complement factors, including a form of C3 that differs from plasmatic C3. This specific C3 isoform can contribute to and enhance complement activation upon bacterial infection (131). Platelets also express various complement receptors, such as C3aR and C5aR, and complement binding evokes an activation response in platelets (131). Additionally, activated platelets can also activate the complement cascade in return (132, 133), amplifying this cascade. Interestingly, C3-deficient mice show a reduction in venous thrombus formation with decreased platelet deposition and also reduced in vitro platelet activation, whereas C5 deficiency does not impact platelet activation but rather affects tissue factor expressed by myeloid cells, which may induce fibrin formation and thus influences venous thrombus formation (134). Also within the lectin pathway, platelets affect the coagulation system: platelets activate MASP-1, which in return can exert a thrombin-like activity, again linking platelet-dependent coagulation and complement-mediated inflammatory responses (135, 136).

Chronic inflammation.

When focusing on inflammation, it is important to distinguish between acute and chronic inflammatory conditions, as platelets appear to change their role in an acute setting from proinflammatory to proresolving, whereas in chronic inflammation this switch is lacking. Indeed, preliminary data from a mouse model used to mimic a chronic inflammation–associated IKK2 activation showed an increased mean platelet volume and increased basal P-selectin surface expression, whereas in vitro platelet aggregation was reduced. The authors thus speculate that chronic inflammation might result in a fatigued or “exhausted” phenotype of platelets and megakaryocytes (137), an observation that is in accordance with the above-mentioned “exhausted” phenotype in chronically ill asthmatic patients. Nonetheless, a study on patients with chronic urticaria suggested an increased P2Y12 expression on platelets from patients compared with controls and also an increased activation response, as measured by soluble P-selectin and platelet aggregation (138, 139). Also in psoriasis, increased mean platelet volume, platelet distribution width, soluble P-selectin levels, and platelet aggregation were observed in patients compared with controls contrasting the notion of an “exhausted” phenotype and instead pointing toward a more distinguished regulation in platelet activation patterns (140). These findings are most likely impacted by the underlying disease phenotype with regard to affected organ, cytokine/chemokine milieu, and duration and severity of the disease.

Inflammation, once provoked, has to be controlled and limited in time and spatial dimensions. Unhindered inflammation can lead to severe organ damage (compare sepsis) or chronification. Control of inflammation together with an active resolution phase is thus needed to restore tissue physiology and remove now-unwanted (apoptotic) inflammatory cells and debris, implicating an interplay between macrophages, platelets, lymphocytes, extracellular matrix components, and progenitor cells (141). Interestingly, platelets have anti-inflammatory properties. Platelets are known to interact with and enhance responses of regulatory T cells, resulting in increased IL-10 levels (142, 143). Regulatory T cells are needed to support macrophage efferocytosis via secretion of IL-13 during resolution of inflammation (144). Also, activated platelets themselves are known to modulate macrophages toward an anti-inflammatory phenotype with increased release of IL-10 and reduced secretion of TNF-α (145). With regard to platelet–inflammatory cell interaction, platelet CLEC-2 and podoplanin inhibit leukocyte infiltration into arthritic joints and thus synovial inflammation and even influence the resolution of autoimmune arthritis in mice (146). Equal results of an anti-inflammatory mode of function were also obtained in a septic inflammation model in which platelet specific CLEC-2 deletion resulted in worsened organ injury (147). As mentioned before, platelets also induce formation of NETs. Even though these DNA releasates are mostly regarded as proinflammatory, they are equally known to limit inflammation by degradation of cytokines and chemokines, such as IL-10, IL-6, MCP-1, MIP-1α and β, IL-1β, and TNF (148), even though these results were debated controversially (149).

Platelets can directly interact with macrophages, leukocytes, and lymphocytes but also secret proresolving signals, so-called specialized proresolving mediators (SPMs) (Fig. 3). These lipoxin mediators are known to be organ protective or influence organ restoration in different disease models, among others abrogating neutrophil infiltration (150, 151). Prominent resolution mediators are, for example, Resolvin D1/D2, Resolvin E1, and maresin 1. Maresin-like lipid mediators are produced by platelets, as well as leukocytes (152). Interestingly, platelets express the SPM receptors ChemR32 (Resolvin E1 receptor), GPR32 (Resolvin D1 receptor), and ALX (lipoxin A4 receptor), and platelet stimulation by maresin 1 leads to a phenotype change in which proinflammatory mediator release from platelets is inhibited, but aggregation in response to ADP and spreading on fibrinogen are enhanced (153, 154). Also, Resolvin D1, and 17-HDHA, a Resolvin precursor, lead to increased platelet aggregation upon ADP stimulation (153). Contrasting data exist with regard to effects of Resolvins on P-selectin surface mobilization in human platelets, as one study found no difference when Resolvin D1 was used in combination with ADP, whereas Resolvin E1 in ADP stimulation in another study led to reduced P-selectin surface mobilization, showing a differential interplay of resolution and platelet activation (153, 155). The interaction of platelets with neutrophils even results in the biosynthesis of maresin 1 in a neutrophil-dependent manner and thus impacts organ damage and restoration in a murine HCl-induced lung injury model, exerting protective effects (156). This finding elicits a dual, somewhat contrasting, role of both platelets and neutrophils in the onset (harmful neutrophil invasion) and termination/resolution of inflammation. Interestingly, also in a model of venous thrombus resolution, which heavily relies on platelet–leukocyte interplay, lack of PECAM-1 provoked an insufficient resolution, although both endothelial and platelet PECAM-1 appear to be implicated in this (157). Consequently, platelets have also been observed to influence organ regeneration in a model of partial hepatectomy in mice. In this study, treatment with a von-Willebrand factor Ab or usage of vWF-deficient mice abolished platelet influx into the liver and dampened regeneration of the remaining liver tissue. This was observed by a decrease in the number of proliferating hepatocytes and a reduction in liver-to-body weight ratio hinting to the potential of platelets not only for inflammatory cell clearance but for also re-establishing of organ integrity (158). In summary, the versatility of platelets during onset and resolution of inflammation is far from being fully understood. The precise mechanisms and actions leading to a switch from proinflammatory recruitment of neutrophils to an anti-inflammatory termination of neutrophil influx and the recruitment and priming of resolving regulatory T cells and macrophages with the release of proresolving mediators remain unclear. One unanswered question so far is whether there is a platelet-intrinsic resolution program that can be activated during the course of inflammation, or if it is a purely passive reaction based on changes of outside mediators and the different priming of the platelets.

FIGURE 3.

Platelet identity. Platelets were originally functionally characterized by their hemostatic potential. However, other functions and a phenotype change can also be observed. Multiple functional regulators are produced, released, or presented by activated platelets and differentially affect organism homeostasis.

FIGURE 3.

Platelet identity. Platelets were originally functionally characterized by their hemostatic potential. However, other functions and a phenotype change can also be observed. Multiple functional regulators are produced, released, or presented by activated platelets and differentially affect organism homeostasis.

Close modal

As platelets seal an injury, it is apparent that they are crucial for barrier functions. This becomes of utmost importance in tissue in which there is not only one schematic stimulus (e.g., vessel wall injury leading to hemostasis), but when multiple hits are combined (such as septic inflammatory bleeding complications). In such setting, the true potential and capability of platelets are needed and challenged. Aside from the above-mentioned functions, platelets are capable of influencing a number of other processes, emphasizing its multipurpose potential. Platelet CLEC-2 is crucial for (lymph-) angiogenesis and also lung development (159, 160). Interestingly, although platelets are important for developmental processes, at early fetal stages they appear to be functionally impaired, also leading to decreased platelet–leukocyte interaction in vivo (13). Already at this very early stage, the question thus arises of whether a “fully functioning” platelet with regard to its hemostatic potential is really needed, or if an intrinsic shift toward specific platelet functions and phenotypes perseveres. With further regard to the ITAM receptor CLEC-2, podoplanin-expressing tumor cells interact with platelet-expressed CLEC-2 (161, 162), and this interaction evolves in the production of proteases, leading to facilitated metastasis (163). In addition, platelets are also involved in wound healing (164) by releasing pro- and antiangiogenic mediators (165) and SDF-1, which impacts progenitor cell recruitment (166). Platelets induce differentiation of endothelial progenitor cells (167), and platelet-derived growth factor affects neointima formation and smooth muscle cell proliferation, which could be of equal importance in tissue and organ regeneration and restructuring (168). With regard to restructuring of tissue, platelets furthermore contain inhibitors of metallopeptidases (TIMP1, 2, and 4), as well as matrix metalloproteinases (MMPs) and disintegrin metalloproteinases (ADAMs), which are likely to contribute to disease related tissue remodeling and reorganization, for example in atherosclerosis (169, 170). Interestingly, MMP-2 was shown to impact soluble CD40L levels (171), which in turn are associated with various inflammatory processes, such as monocyte adhesion and migration and endothelial barrier breakdown (55, 172174).

Platelets are versatile cells undergoing a drastic renaissance of scientific interest. Whereas previous research focused on the role of platelets as merely hemostatic components, it is now clear that these small cellular fragments are equally needed for inflammatory reactions, angiogenesis, wound healing, and resolution of inflammation (Fig. 3).

Possible current therapeutic interventions targeting platelet activation, production, or surface receptors thus may be re-evaluated with regard to inflammatory complications or interventions during the resolution process of such. Also, administration of platelet concentrates has to be carefully re-evaluated and adapted to each patient with regard to its inflammatory background and phenotype.

This work was supported by Interdisciplinary Centre for Clinical Research Muenster Grant SEED12/18 (to A.M.), Deutsche Forschungsgemeinschaft Grants KFO342/1, SCHA1238/7-1, ZA428/14-1, ZA428/12-1, and INST211/604-2, and Interdisciplinary Centre for Clinical Research Muenster Grant Za2/001/18 (to A.Z.).

Abbreviations used in this article:

NET

neutrophil extracellular trap

NLRP3

NACHT, LRR and PYD domains-containing protein 3

Pf4

platelet factor 4

THPO

thrombopoietin.

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The authors have no financial conflicts of interest.