Pentraxins are a superfamily of conserved proteins involved in the acute-phase response and innate immunity. Pentraxin 3 (PTX3), a prototypical member of the long pentraxin subfamily, is a key component of the humoral arm of innate immunity that is essential for resistance to certain pathogens. A regulatory role for pentraxins in inflammation has long been recognized, but the underlying mechanisms remain unclear. Here we report that PTX3 bound P-selectin and attenuated neutrophil recruitment at sites of inflammation. PTX3 released from activated leukocytes functioned locally to dampen neutrophil recruitment and regulate inflammation. Antibodies have glycosylation-dependent regulatory effect on inflammation. Therefore, PTX3, which is an essential component of humoral innate immunity, and immunoglobulins share functional outputs, including complement activation, opsonization and, as shown here, glycosylation-dependent regulation of inflammation.

Activated platelets express ligands, which are recognized by counterreceptors on neutrophils. Here, we show that the ensuing cell-to-cell interaction programs neutrophil phagocytic function, resulting in activated platelet clearance. Neutrophils that have internalized platelets circulate in the blood of patients with acute myocardial infarction, and the extent of platelet clearance correlates with expression of platelet activation, including P-selectin. Activated platelets injected intravenously in experimental animals are detectable in circulating neutrophils 60 minutes after, and within 3 hours, more than 70% circulating neutrophils have internalized platelets. Platelet clearance comprises 2 events: adhesion to neutrophils, which requires divalent cations and depends on P-selectin, on the P-selectin glycoprotein ligand-1 (PSGL-1), and on the CD11b/CD18 ␤2 integrin; and internalization, which is abrogated by the phosphatidylserine-binding protein annexin A5. Adhesion to platelets causes neutrophil degranulation and is blocked by antibodies specific for P-selectin and PSGL-1, either in a synthetic medium in vitro or in the whole blood, therefore in the presence of a physiologic array of plasma cofactors and opsonins. The data suggest that the interaction between circulating platelets and neutrophils influences innate immune functions, possibly contributing to regulate vascular inflammation. IntroductionNeutrophils are recruited to inflamed sites, where they are required for microbial clearance. Neutrophil recruitment is a multistep process, which comprises initial tethering and rolling along the vessel wall, firm adhesion to endothelial cells, and eventual extravasation. It involves consecutively various adhesion molecules, including selectins and ␤2 integrins. [1][2][3][4] Granules of endothelial cells (Weibel-Palade bodies) and of platelets (␣-granules) contain P-selectin. Inflammatory stimuli cause its translocation at the endothelial cell surface. The interaction with the counterreceptor, PSGL-1, prompts leukocyte tethering and rolling and initiates the second phase of the process, firm adhesion. During these events, integrins shift to an active conformation. [5][6][7] Integrin activation depends on the signaling cascade downstream the P-selectin/PSGL-1 interaction. [8][9][10] Platelets adhere and are activated at sites of vascular injury: there, they produce a releasate, some contents of which penetrate and/or interact biochemically with neutrophils. This includes unprocessed free arachidonic acid which can then be transformed into leukotriene A4 and B4. 11-14 Furthermore, activated platelets express P-selectin. Platelet P-selectin guarantees the access of leukocytes to perivascular tissues even when dying or severely damaged endothelial cells fail to sustain leukocyte rolling and adhesion. 15,16 Indeed, endothelial cells surrounding the lesion release signals that amplify the expression of P-selectin on adhering platelets. 17 The P-selectin-dependent interaction of neutrophils and platelets amplifies mut...

Platelet–leukocyte interactions define a basic cell process that is characterized by the exchange of signals between platelets and different types of leukocytes, and that bridges two fundamental physiopathological events: atherothrombosis and immune–inflammatory reactions. When this process takes place at the site of atherosclerotic plaque development or at the site of endothelial injury, platelet-dependent leukocyte recruitment and activation contributes to the inflammatory reaction of the vessel wall, which accounts for the exacerbation of atherosclerosis, and for intimal hyperplasia and plaque instability. Moreover, platelet–leukocyte interactions might have a key role in modulating a wide array of responses of both the innate and adaptive immune systems, thus contributing to the pathogenesis of inflammatory diseases and tissue damage, as well as to host defense.

Diabetes mellitus is associated with platelet hyperactivity, which leads to increased morbidity and mortality from cardiovascular disease. This is coupled with enhanced levels of thromboxane (TX), an eicosanoid that facilitates platelet aggregation. Although intensely studied, the mechanism underlying the relationship among hyperglycemia, TX generation, and platelet hyperactivity remains unclear. We sought to identify key signaling components that connect high levels of glucose to TX generation and to examine their clinical relevance. In human platelets, aldose reductase synergistically modulated platelet response to both hyperglycemia and collagen exposure through a pathway involving ROS/PLCγ2/PKC/p38α MAPK. In clinical patients with platelet activation (deep vein thrombosis; saphenous vein graft occlusion after coronary bypass surgery), and particularly those with diabetes, urinary levels of a major enzymatic metabolite of TX (11-dehydro-TXB 2 [TX-M]) were substantially increased. Elevated TX-M persisted in diabetic patients taking low-dose aspirin (acetylsalicylic acid, ASA), suggesting that such patients may have underlying endothelial damage, collagen exposure, and thrombovascular disease. Thus, our study has identified multiple potential signaling targets for designing combination chemotherapies that could inhibit the synergistic activation of platelets by hyperglycemia and collagen exposure. IntroductionAccelerated atherosclerosis and microvascular disease contribute to the morbidity and mortality associated with diabetes mellitus (DM) (1-3). Vascular inflammation, endothelial dysfunction associated with hyperglycemia, impaired fibrinolysis, and increased coagulation factors as well as abnormal platelet function are typical for DM, contributing to the increased thrombotic events and development of arteriosclerosis (4). Altered platelet function in DM, including altered adhesion and aggregation, may contribute to the pathogenesis of DM vascular complications by promoting microthrombus formation, contributing to enhanced risk of small vessel occlusions and accelerated atherothrombotic diseases (5, 6). Patients with type 2 DM (T2DM) exhibit platelet hyperreactivity both in vitro and in vivo, coupled with biochemical evidence of persistently increased thromboxane-dependent (TX-dependent) platelet activation (7,8). Despite many important studies, the mechanism by which platelets transduce glucose levels into enhanced TX generation independently of endothelial and other blood cell-derived factors remains unclear. Similarly, optimal antiplatelet therapy for DM patients remains to be achieved.Aldose reductase (AR) is the first enzyme of the polyol pathway, and it represents a minor source of glucose utilization, accounting for less than 3% of glucose consumption during euglycemia.