Platelets Guide Leukocytes to Their Sites of Extravasation

• DOI: 10.1371/journal.pbio.1002459
• Publication Date: 2016-05-06T17:40:28Z
• Authors: Gabriele Zuchtriegel; Bernd Uhl; Daniel Puhr-Weste...; Michaela Pörnbacher; Kirsten Lauber; Fritz Krombach; Christoph Andreas...
• Keywords: Blood Platelets; Male; Vasculitis; 0301 basic medicine; Integrins; Membrane Glycoproteins; QH301-705.5; CD40 Ligand; Endothelial Cells; Monocytes; 3. Good health; Mice, Inbred C57BL; Leukocyte Count; P-Selectin; 03 medical and health sciences; Microvessels; Leukocytes; Animals; Biology (General); CD40 Antigens; L-Selectin; Research Article

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.