Finanziert durch die DFG (Emmy Noether-Programm), in Kollaboration mit der WWU Münster
Neutrophils are selectively recruited to tissues that have been injured by infection, trauma, or an autoimmune reaction. Neutrophils constitute the first line of defense against invading bacteria. A defect in neutrophil recruitment, such as seen in leukocyte adhesion deficiency (LAD), is associated with recurrent bacterial infections that can be lethal. On the other hand, inhibition of neutrophil recruitment has protective effects in ischemia-reperfusion injury, abacterial inflammation, and autoimmune disease. Understanding neutrophil activation, signaling, and recruitment can help identify therapeutic targets to selectively inhibit specific functions of neutrophils without affecting others.At sites of inflammation, neutrophils roll along the endothelium of postcapillary venules and collect inflammatory signals, which trigger arrest and transmigration. The first contact between neutrophils and endothelium of postcapillary venules is known as capturing or tethering and is mediated by selectins and their counter-receptors. The selectin family includes three membrane glycoproteins that display different patterns of expression and function. L-selectin is constitutively expressed by the majority of circulating leukocytes and is implicated in lymphocyte homing and leukocyte recruitment to sites of inflammation. P-selectin, which is expressed by activated platelets and activated endothelium, is rapidly translocated to the membrane from intracellular stores and promotes tethering and rolling of leukocytes, and has a predominant role in their recruitment. E-selectin is expressed on inflamed endothelial cells and is a ligand for P-selectin glycoprotein ligand (PSGL)-1, CD44, macrophage antigen (Mac)-1 (αMβ2), and other ligands. In addition to its tethering function, E-selectin also mediates slow rolling in vivo and in vitro and is involved in neutrophil recruitment. Selectin engagement and presentation of chemokines by endothelial cells induce the activation of signaling pathways in neutrophils which cause changes in integrin conformation (inside-out signaling). We studied how selectins activate neutrophils and contribute to leukocyte recruitment.
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