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...

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.

Fibroblast growth factors (FGFs) and their high-affinity receptors [fibroblast growth factor receptors (FGFRs)] contribute to autocrine and paracrine growth stimulation in several nonliver cancer entities. Here we report that at least one member of the FGF8 subfamily (FGF8, FGF17, and FGF18) was up-regulated in 59% of 34 human hepatocellular carcinoma (HCC) samples that we investigated. The levels of the corresponding receptors (FGFR2, FGFR3, and FGFR4) were also elevated in the great majority of the HCC cases. Overall, 82% of the HCC cases showed overexpression of at least one FGF and/or FGFR. The functional implications of the deregulated FGF/FGFR system were investigated by the simulation of an insufficient blood supply. When HCC-1.2, HepG2, or Hep3B cells were subjected to serum withdrawal or the hypoxia-mimetic drug deferoxamine mesylate, the expression of FGF8 subfamily members increased dramatically. In the serum-starved cells, the incidence of apoptosis was elevated, whereas the addition of FGF8, FGF17, or FGF18 impaired apoptosis, which was associated with phosphorylation of extracellular signal-regulated kinase 1/2 and ribosomal protein S6. In contrast, down-modulation of FGF18 by small interfering RNA (siRNA) significantly reduced the viability of the hepatocarcinoma cells. siRNA targeting FGF18 also impaired the cells' potential to form clones at a low cell density or in soft agar. With respect to the tumor microenvironment, FGF17 and FGF18 stimulated the growth of HCC-derived myofibroblasts, and FGF8, FGF17, and FGF18 induced the proliferation and tube formation of hepatic endothelial cells. Conclusion: FGF8, FGF17, and FGF18 are involved in autocrine and paracrine signaling in HCC and enhance the survival of tumor cells under stress conditions, malignant behavior, and neoangiogenesis. Thus, the FGF8 subfamily supports the development and progression of hepatocellular malignancy. (HEPATOLOGY 2011;53:854-864) H epatocellular carcinoma (HCC) is the thirdleading cause of cancer deaths worldwide. 1 Important risk factors for this disease are persistent infections with hepatitis viruses and chronic steatohepatitis due to ethanol abuse and obesity, which contribute to the increasing incidence of HCC in Abbreviations: AHR, aryl hydrocarbon receptor; AKT, protein kinase B; ERK, extracellular signal-regulated kinase; ETS, E twenty-six; FACS, fluorescenceactivated cell sorting; FBS, fetal bovine serum; FCS, fetal colf serum; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; GSK3b, glycogen synthase kinase 3b; HCC, hepatocellular carcinoma; HIF, hypoxia inducible factor; MAP, mitogen-activated protein; MF, myofibroblast; mRNA, messenger RNA; MTF, metal-responsive transcription factor; pERK, phosphorylated extracellular signal-regulated kinase; pGSK3b, phosphorylated glycogen synthase kinase 3b; pS6, phosphorylated S6; qRT-PCR, quantitative reverse-transcriptase polymerase chain reaction; siFGF18, small interfering RNA targeting fibroblast growth factor 18; siRNA, small interfering RNA;...

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.