Platelet Interaction with Innate Immune Cells

Abstract

Platelets are key players in haemostasis and prevent excessive bleeding upon injury. In response to vessel damage, platelets adhere and get activated at sites of injury, leading to recruitment of further platelets and thrombus formation. As injury represents a risk for infection, platelets recruit and activate leukocytes via direct cell-cell contacts and indirectly via cytokines and platelet-derived microvesicles. Activated platelets directly interact with leukocytes via P-selectin (CD62P) interaction with P-selectin glycoprotein ligand 1 (PSGL-1). This initial binding is enhanced by interaction of various other receptors, depending on the leukocyte subtype, leading to mutual activation and local cytokine release (reviewed in [1]), which modulates immune responses.Upon activation platelets release a variety of α-granule-derived cytokines, chemokines and growth factors [2]. The mechanism of packaging inflammatory cargo into α-granules, however, is incompletely understood [3]. Cytokines can be packaged into granules during megakaryopoiesis [4] either via biosynthesis in the megakaryocyte (e.g. platelet factor 4/CXCL4) or via endocytosis from the microenvironment (e.g. albumin) in the bone marrow [3]. Despite lacking a nucleus, platelets can splice and de novo synthesise proteins from megakaryocyte-derived (pre)mRNA as shown for 6]. Via their open canalicular system platelets also take up factors from the circulation. Further platelets can fuse with microvesicles, which leads to intercellular exchanges of chemotactic receptors such as C-C chemokine receptor type 5 (CCR5) and chemokine (C-X-C motif) receptor 4 (CXCR4) [7,8]. Platelet cytokine levels have been demonstrated to be elevated in cancer patients [9,10], indicating either an active uptake of these factors by platelets or disease-related changes in megakaryopoiesis. This suggests that underlying pathologies might influence not only platelet reactivity but also their potential to modulate immune responses. KeywordsPlatelets · Platelet-leukocyte aggregates · P-selectin · Inflammation · Infection · Cardiovascular disease SummaryBeyond 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 pla...

Increased levels of circulating platelet‐derived microparticles are associated with metastatic cutaneous melanoma

“…The exact mechanisms inducing platelet activation and then formation of PMPs in cancer are not well understood, but it seems that there is a direct activation by the tumoral cells releasing procoagulant molecules such as the tissue factor [2] as well as an indirect activation by immune cells. [5,6] In our study, we did not find any association between the plasma level of PMPs and tumor burden using RECIST criteria or radiographic contouring, for all sizes of PMPs in patients with stage IV melanoma. We do not have any clear explanation but we may hypothesise that PMPs reflect the tumor microenvironment, including angiogenesis, inflammatory reaction and antitumoral immunity rather than tumor burden.…”

Measuring and interpreting platelet-leukocyte aggregates

“…Most importantly receptors involved in direct interactions include platelet P-selectin (CD62P) and CD40 ligand (CD40L), as well as PSGL-1, CD40 and Mac-1 (integrin α M β 2 , CD11b/CD18) on leukocytes (2–4). Platelet-leukocyte interactions are further stabilised by crosstalk of numerous additional receptor/ligand pairs that were reviewed previously (1,5) and trigger mutual activation and release of granular content by both platelets and leukocytes, thereby modulating leukocyte function and fine-tuning immune responses (5). Importantly, platelet-leukocyte interactions facilitate leukocyte recruitment and extravasation to sites of inflammation (6,7), promote leukocyte release of pro-inflammatory mediators (8,9), oxidative burst, phagocytosis, release of neutrophil extracellular traps (NETs) (10,11), and may also dampen inflammation under some pathological conditions (12–14).…”

The Two Faces of Thrombosis: Coagulation Cascade and Platelet Aggregation. Are Platelets the Main Therapeutic Target?

“…These adhesion molecules also support in loco eukocyte recruitment and retention, as part of the immunological response to the damage [48]. Thanks to the soluble mediators secreted following activation, platelets may induce transendothelial leukocytes migration.…”

“…However, vessel injury represents a risk for infection, thus recruited platelets may activate leukocytes via direct cell-cell contacts and indirectly via cytokines and/or platelet-derived microvesicles. Interaction between activated platelets and leucocytes occurs by the binding of P-selectin with P-selectin glycoprotein ligand1 (PSGL-1) and is enhanced by interaction with other cofactors and local cytokine release, thus modulating immune responses and local inflammation [41,48]. Platelets store a variety of mediators in the α-granule such as cytokines, chemokines and growth factors.…”