The role of L-selectin in leukocyte recruitment and functions.

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Leukocyte recruitment into inflamed tissue proceeds in a cascade-like fashion. The first contact of leukocytes with the endothelium is mediated by selectins and their counter-receptors, followed by rolling, integrin-mediated arrest, crawling, and transmigration. While rolling, leukocytes collect different inflammatory signals which can activate several pathways leading to integrin activation, leukocyte adhesion to endothelium, and transmigration into inflamed tissue. In the last promotion period, we demonstrated that a subset of P-selectin glycoprotein ligand-1 (PSGL-1) molecules are constitutively associated with L-selectin (cis-interaction) and that the signaling output is dependent on this interaction and the cytoplasmic tail of L-selectin. The L-selectin/PSGL-1-complex signals through different molecules to ultimately result in LFA-1 activation. The PSGL-1/L-selectin complex-induced signaling effects on neutrophil slow rolling and recruitment in vivo demonstrate the functional importance of this pathway. The central topics of this application are the impact of L-selectin and the L-selectin/PSGL-1-complex on leukocyte recruitment and functions as well as the exploration of the signaling pathway downstream of L-selectin and the L-selectin/PSGL-1-complex. To address these topics, we will use gene-deficient mice, retrovirus technology, and biochemical methods. Further understanding of these signaling pathways is necessary in order to therapeutically target specific molecules and inhibit specific functions of leukocytes without affecting others.