Mechanisms of neutrophil activation in inflammation

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Leukocyte recruitment into inflamed tissue proceeds in a cascade-like fashion. The first contact of neutrophils with the endothelium is mediated by selectins and their counter-receptors, followed by rolling and integrin-mediated arrest. While rolling, neutrophils collect different inflammatory signals which can activate several pathways. In addition to activation of neutrophils by G-protein coupled receptors (GPCR) engagement, integrins and selectin ligands are also able to signal into the cell. These signaling pathways may fully activate neutrophils. The signaling pathways following selectin engagement and activation of GPCR and the points of convergence are poorly understood. I propose to investigate which Src kinase and Immunoreceptor Tyrosinbased Activation Motif (ITAM)-containing adaptor molecules are involved in downstream signaling and integrin activation following E-selectin engagement by using gene-deficient mice and biochemical methods. Furthermore, I will investigate which βγ-subunits of GPCRs are involved in neutrophil arrest following GPCR activation by using siRNA and lentivirus technology. The further understanding of these two signaling pathways is necessary in order to therapeutically target specific molecules and inhibit specific functions of neutrophils without affecting others.