Abstract

BackgroundLeukocyte recruitment from the microvasculature to the site of injury or infection is a key event in the inflammatory response. Whereas the principles of this highly complex process have been elucidated in the past decades, it remained poorly understood how these immune cells can ‘find’ their site of extravasation.ObjectiveThe objective of this study was to identify the exit points of myeloid leukocytes in the inflamed microvasculature and to characterize the mechanisms underlying the recruitment of these immune cells to these sites.Materials and methodsInteractions of platelets, neutrophils, inflammatory monocytes, and endothelial cells were analyzed by multi‐color in vivo microscopy in the cremaster muscle of male CX3CR‐1GFP/+ mice (exhibiting fluorescence‐labeled monocytes) upon stimulation with CCL2. Expression profiles of adhesion and signaling molecules in the microvasculature were assessed ex vivo by confocal microscopy in cremasteric tissue whole mounts. Different in vitro assays were used to further characterize the underlying mechanisms.ResultsUpon onset of inflammation, circulating platelets immediately adhered 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 leukocyte PSGL‐1 by P‐selectin initiates conformational changes in surface‐expressed leukocyte integrins via ERK1/2 MAPK which subsequently promote the successive extravasation of neutrophils and inflammatory monocytes to the perivascular tissue. Conversely, blockade of this cellular partnership resulted in misguided, inefficient leukocyte responses.ConclusionHere, we report a previously unrecognized role of platelets as pathfinders navigating neutrophils and inflammatory monocytes to their exit points in the inflamed microvasculature. This platelet‐directed guidance enhances the efficacy of the leukocyte transmigration process and is essential for effective leukocytes responses.Support or Funding InformationSupported by the CRC914 (DFG)

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