Platelets Guide Leukocytes to Their Sites of Extravasation

Abstract

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.

Measuring and interpreting platelet-leukocyte aggregates

“…Simple epifluorescent microscopy coupled with brightfield transillumination has been applied to track platelet-leukocyte interactions over time in some settings (58,61,68). However, this approach is very limited as it offers relatively low spatial and temporal resolution of processes on a cellular level.…”

PSGL-1: A New Player in the Immune Checkpoint Landscape

“…Additionally, PSGL-1 mediates adhesion of neutrophils and monocytes to P-selectin expressed on platelets that become bound to inflamed endothelium. These interactions promote targeted extravasation into tissues by eliciting chemokine secretion by platelets as well as inflammatory mediator production by neutrophils [29]. Platelets also utilize PSGL-1 to adhere to vasculature [30], suggesting that it is important for formation of cellular complexes that function in pathogen clearance.…”

Inhibition of the CD40/CD40L complex protects mice against ALI‐induced pancreas degradation

“…In a first study, we demonstrated that this protein complex has a direct impact on the migration of neutrophils and platelets due to their phenotypic changes (article submitted for publication). Indeed, the interaction between CD40 and its ligand, CD40L, plays a seminal role in cellular communication, especially between platelets, neutrophils, and endothelial cells . Under the influence of this protein complex, neutrophils significantly increased the expression of Mac‐1, a membrane protein involved in cellular communication and neutrophil leukostasis .…”

“…Under the influence of this protein complex, neutrophils significantly increased the expression of Mac‐1, a membrane protein involved in cellular communication and neutrophil leukostasis . In different conditions, the CD40/CD40L protein complex contributes to vascular dysfunction, expression of adhesion molecules, production of inflammatory soluble mediators, leukocyte and platelet adhesion to the vascular wall and migration of these attached cells. By blocking some of these mechanisms, development of ALI is therefore inhibited, thus protecting the lungs from the induction of respiratory distress and the pancreas from acute pancreatitis.…”