Transendothelial migration of lymphocytes across high endothelial venules into lymph nodes is affected by metalloproteinases

The migration of lymphocytes from the bloodstream into lymph nodes (LNs) vi a high endothelial venules (HEVs) is a prerequisite for the detection of pr ocessed antigen on mature dendritic cells and the initiation of immune resp onses. The capture and arrest of lymphocytes from flowing blood is mediated by the multistep adhesion cascade, but the mechanisms that lymphocytes use to penetrate the endothelial lining and the basement membrane of HEVs are poorly understood. Matrix metalloproteinases (MMPs) control the metastatic spread of tumor cells by regulating the penetration blood vessel basement m embranes. In this study, synthetic and natural inhibitors were used to dete rmine the role of MMPs and MMP-related enzymes in regulating lymphocyte ext ravasation in mice. Mice were treated systemically with the hydroxamate-bas ed MMP inhibitor Ro 31-9790 and plasma monitored for effective levels of Ro 31-9790, which block shedding of L-selectin. The total numbers of lymphocy tes recruited into LNs were not altered, but L-selectin levels were higher in mice treated with Ro 31-9790. A reduced number of lymphocytes completed diapedesis and there was an increase in the number of lymphocytes in the en dothelial cell lining, rather than the lumen or the basement membrane of HE Vs. Lymphocyte migration and L-selectin expression in the spleen were not a ltered by Ro 31-9790 treatment. Two MMP Inhibitors, TIMP1 and Ro 32-1541, d id not block L-selectin shedding and had no effect on lymphocyte migration across HEVs. These results suggest that metalloproteinase activity is requi red for lymphocyte transmigration across HEVs into LNs and provide evidence for the concept that metalloproteinases are important players in some form s of transendothelial migration. (C) 2001 by The American Society of Hemato logy.