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Effective immune responses require the directed migration of leukocytes from the vasculature to the site of injury or infection. How immune cells “find” their site of extravasation remains largely obscure. Here, we identified a previously unrecognized role of platelets as pathfinders guiding leukocytes to their exit points in the microvasculature: upon onset of inflammation, circulating platelets were found to immediately adhere at distinct sites in venular microvessels enabling these cellular blood components to capture neutrophils and, in turn, inflammatory monocytes via CD40-CD40L-dependent interactions. In this cellular crosstalk, ligation of PSGL-1 by P-selectin leads to ERK1/2 MAPK-dependent conformational changes of leukocyte integrins, which promote the successive extravasation of neutrophils and monocytes to the perivascular tissue. Conversely, blockade of this cellular partnership resulted in misguided, inefficient leukocyte responses. Our experimental data uncover a platelet-directed, spatiotemporally organized, multicellular crosstalk that is essential for effective trafficking of leukocytes to the site of inflammation. [ABSTRACT FROM AUTHOR]

It has been suggested that engineered nanomaterials (ENM), once arrived in the circulation, may affect the cardiovascular system. The aim of thisin vivostudy was to screen major cardiovascular effects of acute systemic administration of a panel of five nanomaterials, TiO2anatase (NM-101), TiO2rutile (NM-104), ZnO (NM-110), SiO2(NM-200) and Ag (NM-300). Mice were anesthetized and the ENM were injected at a dose of 1 mg/kg via a catheter placed in the left femoral artery. Hemodynamic parameters were determined by invasive measurement of blood pressure and non-invasive measurement of heart rate. Ten minutes after injection of the ENM, the formation of light/dye-induced thrombi was assessed in the cremasteric microcirculation by intravital microscopy. In addition, the numbers of rolling, firmly adherent and transmigrated leukocytes were recorded in postcapillary cremasteric venules over a time period of 120 min after injection of ENM by intravital microscopy. The systemic administration of a single dose of the ENM tested did not dramatically alter hemodynamic parameters or affect early steps of leukocyte recruitment. However, the presence of circulating TiO2anatase, but not of TiO2rutile, SiO2, ZnO or Ag nanoparticles, significantly accelerated thrombus formation in the murine microcirculation. Moreover, TiO2anatase but not TiO2rutile nanoparticles increased murine platelet aggregationin vitro. Taken together, only one of the five systemically administered ENM, TiO2anatase, affected hemostasis, whereas none of the ENM tested in this screening study dramatically modulated hemodynamic parameters or early steps of leukocyte recruitment. [ABSTRACT FROM PUBLISHER]

Initial observations suggested that C-C motif chemokines exclusively mediate Chemotaxis of mononuclear cells. In addition, recent studies also implicated these chemotactic cytokines in the recruitment of neutrophils. The underlying mechanisms remained largely unknown. Using in vivo microscopy on the mouse cremas-ter muscle, intravascular adherence and subsequent paracellular transmigration of neutrophils elicited by the chemokine (C-C motif) ligand 3 (CCL3, synonym MIP-1&agr;) were significantly diminished in mice with a deficiency of the chemokine (C-C motif) receptor 1 (Ccr1-/-) or 5 (Ccr5-/-). Using cell-transfer techniques, neutrophil responses required leukocyte CCR1 and nonleukocyte CCR5. Furthermore, neutrophil extravasation elicited by CCL3 was almost completely abolished on inhibition of G protein-receptor coupling and PI3K&ggr;-dependent signaling, while neutrophil recruitment induced by the canonical neutrophil attractants chemokine (C-X-C motif) ligand 1 (CXCL1, synonym KC) or the lipid mediator platetelet-activating factor (PAF) was only partially reduced. Moreover, Ab blockade of &bgr;2 integrins, of «, integrins, or of their putative counter receptors ICAM-1 and VCAM-1 significantly attenuated CCL3-, CXCL1-, or PAF-elicited intravascular adherence and paracellular transmigration of neutrophils. These data indicate that the C-C motif chemokine CCL3 and canonical neutrophil attractants exhibit both common and distinct mechanisms for the regulation of intravascular adherence and transmigration of neutrophils. [ABSTRACT FROM AUTHOR]