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.
Highlights
Lymphangiogenesis plays a pivotal role in diverse pathological conditions
We demonstrate here that galectin-8 is highly upregulated in pathological corneas and plays a critical role in the process of lymphangiogenesis
The striking finding that several other members of galectin family including galectins-1 and 3, which are known to promote hemangiogenesis, did not promote lymphatic endothelial cell (LEC) sprouting suggests that galectin-8-mediated LEC sprouting involves the affinity of N-carbohydrate recognition domain (CRD) of galectin-8 for 30-sialylated galactosides that is unique among animal galectins[11,12,13]
Summary
Lymphangiogenesis plays a pivotal role in diverse pathological conditions. Here, we demonstrate that a carbohydrate-binding protein, galectin-8, promotes pathological lymphangiogenesis. Recent studies have demonstrated that the members of the galectin family of mammalian lectins characterized by a carbohydrate recognition domain (CRD) with affinity for b-galactoside-containing glycans, play a critical role in hemangiogenesis. In this respect, we have shown that a member of galectin family, galectin-3, modulates VEGF-A-induced angiogenic response by binding via its CRD to the N-glycans of integrin avb[3] and VEGFR-2 and subsequently activating angiogenic signalling pathways[9,10]. In vitro studies have shown that galectin-8 binds to podoplanin (PDPN) and that the lectin promotes adhesion and haptotaxis of lymphatic endothelial cells (LECs)[14]. VEGFR-3 and PDPN are glycosylated like most cell surface receptors, more direct studies on the role of carbohydratedependent function of integrins, PDPN and VEGF-C/VEGFR-3 in the regulation of lymphangiogenesis have not been reported
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