L-selectin mediates the initial adhesion of lymphocytes to high endothelial venules (HEV) in lymph nodes during the process of lymphocyte homing. It also functions in leukocyte-endothelial interactions underlying the trafficking of leukocytes into chronic inflammatory sites. L-selectin functions as a lectin-like receptor by recognizing a discrete set of HEV-expressed ligands including GlyCAM-1, CD34, and podocalyxin. These ligands bear O-linked carbohydrate chains that are sulfated, fucosylated and sialylated. All three of these modifications are required for optimal recognition by L-selectin. A detailed analysis of GlyCAM-1 and CD34 has revealed that tile recognition determinant for L-selectin binding is a sulfated structure known as 6-sulfo sLex, a tetrasaccharide that possesses a sulfate ester on the C-6 position of N-acetylglucosamine. In the search for the sulfotransferase that elaborates this critical modification within HEV, the Rosen laboratory has cloned a family of GlcNAc-6-O-sulfotransferases. Two of these, known as GST-2 and GST-3, are present in HEV. GST-3 has been given the name HEC-GlcNAc6ST because of its highly restricted expression in high endothelial cells (HEC) of HEV. The direct involvement of HEC-GlcNAc6ST in elaborating L-selectin ligands has been established by disrupting this gene in mice. HEC-GIcNAc6ST knockout mice exhibit a significant but incomplete loss of HEV-expressed ligands for L-selectin and an impairment of lymphocyte homing to lymph nodes. The present grant will continue the study of HEC-GlcNAc6ST and the related enzyme, GST-2, with respect to their functions in lymphocyte homing and inflammatory leukocyte trafficking.
The specific aims are: 1) To determine the contribution of HEC-GIcNAc6ST to the activity of L-selectin ligands generated in situ; 2) To determine the expression of HEC-GlcNAc6ST in activated endothelium at sites of inflammation; 3) To determine the contribution of HEC-GlcNAc6ST to leukocyte recruitment and disease in mouse models of chronic inflammation; and 4) To determine the contribution of GST-2 to the generation of L-selectin ligands. Gaining further understanding of these sulfotransferases has considerable biomedical relevance, because these enzymes are potential therapeutic targets for blocking inflammatory diseases.
|Patnode, Michael L; Bando, Jennifer K; Krummel, Matthew F et al. (2014) Leukotriene B4 amplifies eosinophil accumulation in response to nematodes. J Exp Med 211:1281-8|
|Patnode, Michael L; Yu, Shin-Yi; Cheng, Chu-Wen et al. (2013) KSGal6ST generates galactose-6-O-sulfate in high endothelial venules but does not contribute to L-selectin-dependent lymphocyte homing. Glycobiology 23:381-94|
|Patnode, Michael L; Cheng, Chu-Wen; Chou, Chi-Chi et al. (2013) Galactose 6-O-sulfotransferases are not required for the generation of Siglec-F ligands in leukocytes or lung tissue. J Biol Chem 288:26533-45|
|Zhang, Yafeng; Chen, Yi-Chun Maria; Krummel, Matthew F et al. (2012) Autotaxin through lysophosphatidic acid stimulates polarization, motility, and transendothelial migration of naive T cells. J Immunol 189:3914-24|
|Arata-Kawai, Hanayo; Singer, Mark S; Bistrup, Annette et al. (2011) Functional contributions of N- and O-glycans to L-selectin ligands in murine and human lymphoid organs. Am J Pathol 178:423-33|
|Kerr, Sheena C; Fieger, Claudia B; Snapp, Karen R et al. (2008) Endoglycan, a member of the CD34 family of sialomucins, is a ligand for the vascular selectins. J Immunol 181:1480-90|
|Kanda, Hidenobu; Newton, Rebecca; Klein, Russell et al. (2008) Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs. Nat Immunol 9:415-23|
|Nawroth, Roman; van Zante, Annemieke; Cervantes, Sara et al. (2007) Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS One 2:e392|
|Veerman, Krystle M; Williams, Michael J; Uchimura, Kenji et al. (2007) Interaction of the selectin ligand PSGL-1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs. Nat Immunol 8:532-9|
|Lum, David H; Tan, Jenille; Rosen, Steven D et al. (2007) Gene trap disruption of the mouse heparan sulfate 6-O-endosulfatase gene, Sulf2. Mol Cell Biol 27:678-88|
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