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.
Highlights
Directed migration of leukocytes from the vasculature to the site of injury or infection is a prerequisite for effective immune responses
Endothelial cell interactions of these immune cells were analyzed in the inflamed microvasculature of the cremaster muscle of “monocyte-reporter mice” (CX3CR1GFP/+ mice; exhibiting fluorescence-labeled monocytes as well as NK cells and T cell subsets [20]) by using multichannel in vivo microscopy (S1 Video)
Classical/inflammatory (GFPlow leukocytes) and nonclassical monocytes in CXC3CR1GFP/+ mice were differentiated by their relative fluorescence intensity as described previously [21,22]
Summary
Directed migration of leukocytes from the vasculature to the site of injury or infection is a prerequisite for effective immune responses. To enter the site of inflammation, leukocytes “roll” on the luminal surface of microvascular endothelial cells before these immune cells stabilize their interactions and adhere to the inner vessel wall. Extensive signaling between arrested leukocytes and the endothelium triggers adhesion strengthening and leads to intraluminal crawling of these blood cells along the microvasculature in search for suitable sites of extravasation. Leukocytes squeeze between adjacent endothelial cells, penetrate the perivenular basement membrane, and subendothelially locomote to gaps between pericytes from where they migrate into the interstitial tissue [2,3,4,5,6]. Whereas the basic principles of this multistep cascade have been characterized in the past decades, it remains poorly understood how leukocytes can “find” their sites of extravasation
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