title: Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3.
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.
authors.affiliation: Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, USA.|New England Eye Center/Department of Ophthalmology, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Chen
authors.affiliation: New England Eye Center/Department of Ophthalmology, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Cao
authors.affiliation: New England Eye Center/Department of Ophthalmology, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sugaya
authors.affiliation: New England Eye Center/Department of Ophthalmology, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Lopez
authors.affiliation: New England Eye Center/Department of Ophthalmology, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Sendra
authors.affiliation: New England Eye Center/Department of Ophthalmology, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Laver
authors.affiliation: Department of Laboratory Medicine, Section of Microbiology Immunology and Glycobiology, Sölvegatan, Lund University, Lund SE-22184, Sweden.
authors.forename: Hakon
authors.initials: H
authors.lastname: Leffler
authors.affiliation: Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Lund SE-22100, Sweden.
authors.forename: Ulf J
authors.initials: UJ
authors.lastname: Nilsson
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.|Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Fu
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.|Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Song
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.|Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.affiliation: New England Eye Center/Department of Ophthalmology, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Hamrah
authors.affiliation: Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, USA.|New England Eye Center/Department of Ophthalmology, Tufts University, Boston, Massachusetts 02111, USA.|Department of Developmental, Molecular and Chemical Biology, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Noorjahan
authors.initials: N
authors.lastname: Panjwani
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003315:Cornea / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D037161:Galectins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D016023:Integrins / Q000378:metabolism*; D042583:Lymphangiogenesis / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D042582:Vascular Endothelial Growth Factor C / Q000494:pharmacology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*; D000098853:Podoplanin
chemical_list: D037161:Galectins; D016023:Integrins; D008562:Membrane Glycoproteins; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C091991:LGALS8 protein, human; C117468:PDPN protein, human