Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway.

Abstract

Abstract. Leukocyte recruitment is a key step in the inflammatory reaction. Several changes in the cell morphology take place during lymphocyte activation and migration: spheric-shaped resting T cells become polarized during activation, developing a well defined cytoplasmic projection designated as cellular uropod. We found that the chemotactic and proinflammatory chemokines RANTES, MCP-1, and, to a lower extent, MIP-la, MIP-113, and IL-8, were able to induce uropod formation and ICAM-3 redistribution in T lymphoblasts adhered to ICAM-1 or VCAM-1. A similar chemokine-mediated effect was observed during T cells binding to the fibronectin fragments of 38-and 80-kD, that contain the binding sites for the integrins VLA-4 and VLA-5, respectively. The uropod structure concentrated the ICAM-3 adhesion molecule (a ligand for LFA-1), and emerged to the outer milieu from the area of contact between lymphocyte and protein ligands. In addition, we found that other adhesion molecules such as ICAM-1, CD43, and CD44, also redistributed to the lymphocyte uropod upon RANTES stimulation, whereas a wide number of other cell surface receptors did not redistribute. Chemokines displayed a selective effect among different T cell subsets; MIP-1[3 had more potent action on CD8 ÷ T cells and tumor infiltrating lymphocytes (TIL), whereas RANTES and MIP-let targeted selectively CD4 ÷ T cells. We have also examined the involvement of cAMP signaling pathway in uropod formation. Interestingly, several cAMP agonists were able to induce uropod formation and ICAM-3 redistribution, whereas H-89, a specific inhibitor of the cAMPdependent protein kinase, abrogated the chemokinemediated uropod formation, thus pointing out a role for cAMP-dependent signaling in the development of this cytoplasmic projection. Since the lymphocyte uropod induced by chemokines was completely abrogated by

Annexin 1 Binds to U937 Monocytic Cells and Inhibits Their Adhesion to Microvascular Endothelium: Involvement of the α4β1 Integrin

“…During this process, chemoattractant receptors and integrins are redistributed in different areas of the plasma membrane. Whereas in most cases chemoattractant receptors are concentrated at the leading edge of the cells (34), integrins are redistributed at the trailing edge or uropod (35,36). In SDF-1-activated polarized U937 cells, CXCR4 receptors become concentrated at one pole of the cell, which is almost completely devoid of ANX1.…”

CD2 molecules redistribute to the uropod during T cell scanning: Implications for cellular activation and immune surveillance

“…Given that the MTOC and the Golgi apparatus colocalize, the secretion of soluble mediators is directed toward the ligated cell surface (7). Moreover, chemokine receptors responsible for the directionality of the migration along a gradient of chemoattractants are concentrated within the leading edge (8). In contrast, the uropod mediates important adhesion functions, as suggested by accumulation of a notable number of adhesion molecules including ICAM-1, CD44, CD43, P-selective glycoprotein ligand 1 (PSGL-1), and L-selectin during migration (9,10).…”

Trypanosoma cruzi-elicited CD8+ T cell-mediated myocarditis: chemokine receptors and adhesion molecules as potential therapeutic targets to control chronic inflammation?

“…Both recruitment and migration are multistep processes that depend on the nature and state of activation of the leukocytes, involve pro-inflammatory cytokines, adhesion molecules, and extracellular matrix (ECM) components, being co-ordinated by a mosaic of chemoattractant molecules named chemokines (Shimizu & Shaw 1991, Nathan & Sporn 1991, Del Pozo et al 1995, Gilat et al 1996, Sallusto et al 2000, Gerard & Rollins 2001, Moser & Loestscher 2001.…”