Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3

Wei-Sheng Chen, Zhiyi Cao, Satoshi Sugaya, Maria J. Lopez, Victor G. Sendra, Nora Laver, Hakon Leffler, Ulf J. Nilsson, Jianxin Fu, Jianhua Song, Lijun Xia, Pedram Hamrah and Noorjahan Panjwani ()
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Wei-Sheng Chen: Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University
Zhiyi Cao: Tufts University
Satoshi Sugaya: Tufts University
Maria J. Lopez: Tufts University
Victor G. Sendra: Tufts University
Nora Laver: Tufts University
Hakon Leffler: Section of Microbiology Immunology and Glycobiology, Sölvegatan, Lund University
Ulf J. Nilsson: Centre for Analysis and Synthesis, Lund University
Jianxin Fu: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation
Jianhua Song: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation
Lijun Xia: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation
Pedram Hamrah: Tufts University
Noorjahan Panjwani: Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University

Nature Communications, 2016, vol. 7, issue 1, 1-19

Abstract: Abstract Lymphangiogenesis plays a pivotal role in diverse pathological conditions. Here, we demonstrate that a carbohydrate-binding protein, galectin-8, promotes pathological lymphangiogenesis. Galectin-8 is markedly upregulated in inflamed human and mouse corneas, and galectin-8 inhibitors reduce inflammatory lymphangiogenesis. In the mouse model of corneal allogeneic transplantation, galectin-8-induced lymphangiogenesis is associated with an increased rate of corneal graft rejection. Further, in the murine model of herpes simplex virus keratitis, corneal pathology and lymphangiogenesis are ameliorated in Lgals8−/− mice. Mechanistically, VEGF-C-induced lymphangiogenesis is significantly reduced in the Lgals8−/− and Pdpn−/− mice; likewise, galectin-8-induced lymphangiogenesis is reduced in Pdpn−/− mice. Interestingly, knockdown of VEGFR-3 does not affect galectin-8-mediated lymphatic endothelial cell (LEC) sprouting. Instead, inhibiting integrins α1β1 and α5β1 curtails both galectin-8- and VEGF-C-mediated LEC sprouting. Together, this study uncovers a unique molecular mechanism of lymphangiogenesis in which galectin-8-dependent crosstalk among VEGF-C, podoplanin and integrin pathways plays a key role.

Date: 2016
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DOI: 10.1038/ncomms11302

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