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Sphingosine-1-Phosphate Agonists Increase Macrophage Homing, Lymphocyte Contacts, and Endothelial Junctional Complex Formation in Murine Lymph Nodes

Irwin I. Singer^1,*, Min Tian^*, L. Alexandra Wickham, Jeffrey Lin, Scaria S. Matheravidathu, Michael J. Forrest, Suzanne Mandala^* and Elizabeth J. Quackenbush^1,

^* Immunology and Rheumatology, Pharmacology, and Cardiovascular Disease, Merck and Co., Inc., Merck Research Laboratories, Rahway, NJ 07065

The sphingosine-1-phosphate (S1P) receptor agonist, phosphorylated FTY720 (FTY-P), causes lymphopenia, lymphocyte sequestration in mesenteric lymph nodes (MLNs), and immunosuppression. Using multiple techniques to analyze MLN cells harvested from mice treated with S1P receptor agonists, we saw a redistribution of lymphocytes out of nodal sinuses and an expansion of follicles. Although changes in circulating monocytes were not observed with overnight exposure to FTY720, we saw a significant increase in S1P receptor 1 (S1P₁)-expressing CD68⁺ macrophages in subcapsular sinuses of FTY-P-treated MLNs. This was confirmed by quantitative analysis of F4/80⁺ cells in MLN suspensions. The sinus volume and number of S1P₁-positive cells within sinuses were also increased by FTY-P. High endothelial venules and lymphatic endothelium expressed high levels of S1P₁, and treatment with FTY-P resulted in intense staining and colocalization of CD31, -catenin, and zona occludens 1 in junctions between sinus cells. Transmission electron microscopy showed that FTY-P greatly reduced lymphocyte microvilli and increased cell-cell contacts in the parenchyma. Immunoelectron microscopy revealed that intranodal lymphocytes lacked surface expression of S1P₁, whereas S1P₁ was evident on the surface and within the cytoplasm of macrophages, endothelial cells, and stromal cells. This subcellular pattern of intranodal receptor distribution was unchanged by treatment with FTY-P. We conclude that S1P₁ agonists have profound effects on macrophages and endothelial cells, in addition to inducing lymphopenia.

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