Beyond their important role in hemostasis, platelets play a crucial role in inflammatory diseases. This becomes apparent during sepsis, where platelet count and activation correlate with disease outcome and survival. Sepsis is caused by a dysregulated host response to infection, leading to organ dysfunction, permanent disabilities, or death. During sepsis, tissue injury results from the concomitant uncontrolled activation of the complement, coagulation, and inflammatory systems as well as platelet dysfunction. The balance between the systemic inflammatory response syndrome (SIRS) and the compensatory anti-inflammatory response (CARS) regulates sepsis outcome. Persistent thrombocytopenia is considered as an independent risk factor of mortality in sepsis, although it is still unclear whether the drop in platelet count is the cause or the consequence of sepsis severity. The role of platelets in sepsis development and progression was addressed in different experimental in vivo models, particularly in mice, that represent various aspects of human sepsis. The immunomodulatory function of platelets depends on the experimental model, time, and type of infection. Understanding the molecular mechanism of platelet regulation in inflammation could bring us one step closer to understand this important aspect of primary hemostasis which drives thrombotic as well as bleeding complications in patients with sterile and infectious inflammation. In this review, we summarize the current understanding of the contribution of platelets to sepsis severity and outcome. We highlight the differences between platelet receptors in mice and humans and discuss the potential and limitations of animal models to study platelet-related functions in sepsis.

Beyond their traditional role in haemostasis and thrombosis, platelets are increasingly recognised as immune modulatory cells. Activated platelets and platelet-derived microparticles can bind to leukocytes, which stimulates mutual activation and results in rapid, local release of platelet-derived cytokines. Thereby platelets modulate leukocyte effector functions and contribute to inflammatory and immune responses to injury or infection. Platelets enhance leukocyte extravasation, differentiation and cytokine release. Platelet-neutrophil interactions boost oxidative burst, neutrophil extracellular trap formation and phagocytosis and play an important role in host defence. Platelet interactions with monocytes propagate their differentiation into macrophages, modulate cytokine release and attenuate macrophage functions. Depending on the underlying pathology, platelets can enhance or diminish leukocyte cytokine production, indicating that platelet-leukocyte interactions represent a fine balanced system to restrict excessive inflammation during infection. In atherosclerosis, platelet interaction with neutrophils, monocytes and dendritic cells accelerates key steps of atherogenesis by promoting leukocyte extravasation and foam cell formation. Platelet-leukocyte interactions at sites of atherosclerotic lesions destabilise atherosclerotic plaques and promote plaque rupture. Leukocytes in turn also modulate platelet function and production, which either results in enhanced platelet destruction or increased platelet production. This review aims to summarise the key effects of platelet-leukocyte interactions in inflammation, infection and atherosclerosis.

Vascular disease is a progressive inflammatory condition fuelled by an unhealthy lifestyle of physical inactivity, cholesterol-rich diet, and smoking. Together with endogenous factors such as age, gender, and autoimmune status, an unhealthy lifestyle fosters a pro-inflammatory and pro-thrombotic milieu, which can lead to endothelial dysfunction, atherosclerotic plaque formation and vascular obstruction or degradation of the subendothelial matrix. Platelet-leukocyte interplay represents an important feature in this context. Platelets get activated in a pro-inflammatory and pro-thrombotic microenvironment and readily interact with innate and adaptive immune cells alike. Even though platelet affinity for physical cell-cell contact is highest with monocytes/macrophages and neutrophils, platelets also avidly interact with lymphocytes by soluble mediators. Platelet-leukocyte crosstalk regulates essential immune responses, supporting leukocyte recruitment at sites of vascular insult, promoting proliferation and differentiation of leukocytes and enhancing pro-inflammatory effector functions such as cytokine and reactive oxygen production. However, under certain conditions platelet-leukocyte interplay also dampens the inflammatory process. Crosstalk of platelet and leukocytes thus represents a driving force in vascular disease. In this review, we highlight the impact of various risk factors for vascular disease on platelet-leukocyte interactions and discuss the underlying mechanisms of platelet-mediated changes in immune responses and the effect of immune cells on the haemostatic system. As the underlying pathologies differ between vascular diseases, we summarize our current knowledge on platelet-leukocyte interplay in chronic vascular diseases such as abdominal aortic aneurysm, peripheral and coronary artery disease as well as acute vascular diseases such as ischaemic stroke and venous thromboembolism.

Platelets, besides their specialised role in haemostasis and atherothrombosis, actively modulate innate and adaptive immune responses with crucial roles in immune surveillance, inflammation and host defence during infection. An important prerequisite for platelet-mediated changes of immune functions involves direct engagement with different types of leukocytes. Indeed, increased platelet-leukocyte aggregates (PLAs) within the circulation and/or locally at the site of inflammation represent markers of many thrombo-inflammatory diseases, such as cardiovascular diseases, acute lung injury, renal and cerebral inflammation. Therefore, measurement of PLAs could provide an attractive and easily accessible prognostic and/or diagnostic tool for many diseases. To measure PLAs in different (patho-)physiological settings in human and animal models flow cytometric and microscopic approaches have been applied. These techniques represent complementary tools to study different aspects relating to the involvement of leukocyte subtypes and molecules, as well as location of PLAs within tissues, dynamics of their interactions and/or dynamic changes in leukocyte and platelet behaviour. This review summarises various approaches to measure and interpret PLAs and discusses potential experimental factors influencing platelet binding to leukocytes. Furthermore, we summarise insights gained from studies regarding the underlying mechanism of platelet-leukocyte interactions and discuss implications of these interactions in health and disease.

Objective—: A growing body of evidence indicates that platelets contribute to the onset and progression of atherosclerosis by modulating immune responses. We aimed to elucidate the effects of oxidized low-density lipoprotein (OxLDL) on platelet–monocyte interactions and the consequences of these interactions on platelet phagocytosis, chemokine release, monocyte extravasation, and foam cell formation. Approach and Results—: Confocal microscopy and flow cytometric analysis revealed that in vitro and in vivo stimulation with OxLDL resulted in rapid formation of platelet–monocyte aggregates, with a preference for CD16+ monocyte subsets. This platelet–monocyte interaction facilitated OxLDL uptake by monocytes, in a process that involved platelet CD36–OxLDL interaction, release of chemokines, such as CXC motif ligand 4, direct platelet–monocyte interaction, and phagocytosis of platelets. Inhibition of cyclooxygenase with acetylsalicylic acid and antagonists of ADP receptors, P2Y1 and P2Y12, partly abrogated OxLDL-induced platelet–monocyte aggregates and platelet-mediated lipid uptake in monocytes. Platelets also enhanced OxLDL-induced monocyte transmigration across an endothelial monolayer via direct interaction with monocytes in a transwell assay. Importantly, in LDLR ^−/− mice, platelet depletion resulted in a significant decrease of peritoneal macrophage recruitment and foam cell formation in a thioglycollate-elicited peritonitis model. In platelet-depleted wild-type mice, transfusion of ex vivo OxLDL-stimulated platelets induced monocyte extravasation to a higher extent when compared with resting platelets. Conclusions—: Our results on OxLDL-mediated platelet–monocyte aggregate formation, which promoted phenotypic changes in monocytes, monocyte extravasation and enhanced foam cell formation in vitro and in vivo, provide a novel mechanism for how platelets potentiate key steps of atherosclerotic plaque development and plaque destabilization.

Platelets are key players in haemostasis and represent a pivotal link between inflammation, immunity and atherogenesis. Depending on the (patho)physiological environment platelets modulate various leukocyte functions via release of inflammatory mediators and direct cell-cell interactions. Elevated levels of circulating platelet-leukocyte aggregates are found in patients suffering from several thrombotic or inflammatory conditions. Platelet-monocyte and platelet-neutrophil interaction can trigger pro- and anti-inflammatory responses and modulate effector functions of all leukocyte subpopulations. These platelet-mediated immune responses have implications for the progression of cardiovascular diseases and also play a crucial role during infections, cancer, transplantations and other inflammatory diseases of several organs. Antiplatelet therapy including the COX inhibitor aspirin and/or ADP receptor P2Y₁₂ inhibitors such as clopidogrel, prasugrel and ticagrelor are the therapy of choice for various cardiovascular complications. Both aspirin and P2Y₁₂ inhibitors attenuate platelet-leukocyte interactions, thereby also modulating immune responses. This may have beneficial effects in some pathological conditions, while it might be detrimental in others. This review aims to summarise the current knowledge on platelet-leukocyte interactions and the impact of aspirin and P2Y₁₂ inhibition on platelet-mediated immune responses and to give an overview on the effects of antiplatelet therapy on platelet-leukocyte interplay in various diseases.