Lymphocyte recirculation is known to be regulated by adhesion molecules and signaling by chemokines. CCL21 (also known as SLC or 6Ckine) is a chemokine constitutively expressed in endothelial cells of the high endothelial venules (HEV) of lymph nodes.1,2) CCR7, the corresponding receptor for CCL21, is known to be expressed on T and B cells. 3,4) CCR7 is also expressed on dendritic cells (DC), and CCL21 has been shown to be involved in DC trafficking to draining lymph nodes.
5)Studies on lipid mediators such as sphingosine-1-phosphate (S1P) have demonstrated a significant effect of S1P on the process of lymphocyte recirculation. Signaling by S1P has been demonstrated to be involved in the lymphocyte egress from lymphoid organs. [6][7][8] An immunosuppressant drug, FTY720, has been shown to bind and activate S1P receptors including S1P 1 (also known as Edg1), and to inhibit lymphocyte egress.9,10) S1P exhibits chemotactic activity toward lymphocytes in a standard in vitro chemotaxis assay. 7,11,12) Interestingly, S1P and FTY720 enhance the migration of splenic T cells toward CCL19 (another ligand for CCR7). 13) Another study has also demonstrated that FTY720 enhanced CCL21-induced chemotaxis of T cells.14) S1P receptors and chemokine receptors are G protein-coupled receptors (GPCR).15) These results suggested the presence of crosstalk between S1P and chemokine signaling pathways.Recent studies suggested that chemorepulsive signals play a role in the regulation of chemotaxis. For example, apoptotic cells have been demonstrated to release chemotactic factors, such as ATP and uridine 5Ј-triphosphate (UTP), for macrophages that clear apoptotic cells. These factors, which are sensed through P2Y 2 receptors, induce macrophage chemotaxis toward apoptotic cells.16) Although neutrophils also express P2Y 2 receptors, 16) neutrophil migration toward apoptotic cells is inhibited by chemorepulsive factors such as lactoferrin, which is released from apoptotic cells.
17)Through this mechanism, excessive inflammation is avoided in tissues in which apoptosis occurs.Lysophosphatidic acid (LPA) is a lysophospholipid mediator. The S1P and LPA receptors belong to the same family among GPCRs.18) LPA is generated through hydrolysis of lysophosphatidylcholine (LPC) by lysophospholipase D (lysoPLD), or by an enzyme exhibiting similar activity called autotaxin (ATX). 19,20) Another pathway is the hydrolysis of phosphatidic acid (PA) by phospholipase A 1 or A 2 .21,22) LPA can be generated outside of cells upon stimulation of some types of cell lines and blood platelets. 23,24) LPA signals are transmitted through cell surface-specific GPCRs or cytosolic/nuclear peroxisome proliferator-activated receptor gamma (PPARg).25) Cell surface LPA receptors of the endothelial differentiation gene (EDG) family comprise LPA 1 /Edg-2, LPA 2 /Edg-4, and LPA 3 /Edg-7. [26][27][28] There are other receptors, LPA 4 /GPR23, 29) LPA 5 , 30) and LPA 6 , 31) which are structurally distinct from receptors of the EDG family.Human blood lymphocytes and leukocytes,...