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.

Inflammation‐induced lymphatic architecture and bone turnover changes are ameliorated by irisin treatment in chronic inflammatory bowel disease

“…The amorphous podoplanin hi regions appeared restricted to the mucosal compartment when present; however, it is unknown whether these regions are an expansion of the lymphatic capillaries in the lamina propria or a breach in the lymphatic endothelium below the mucosa into the lamina propria. Furthermore, podoplanin's function is equivocal, but supporting evidence of its functional role includes interaction with galectin-8 in lymphatic endothelium to support cell adhesion to the surrounding extracellular matrix, lymphangiogenesis, and lymphocyte trafficking through podoplanin interactions with C-C motif chemokine ligand 21 (CCL21) (37)(38)(39). It is unknown whether this lymphatic proliferation is driven by local parenchymal tissue hydrodynamic alterations, leukocyte activation and migration, or production and transport of inflammatory cytokines (40).…”

Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium

“…Although the podoplanin-mediated signaling pathway is not sufficiently understood, the expression of podoplanin is cognate to lymphatic endothelial cells; and inflammatory lymphangiogenesis is attenuated if podoplanin activity is lacking [59–61]. Podoplanin deficiency impairs cardiac development [59], while continuous expression of podoplanin into adulthood is required to maintain functional lymphatic vasculature [57, 62, 63].…”

New insights into mononuclear phagocyte biology from the visual system

“…To overcome the aforementioned inhibitory activities in the cornea, certain factors are switched on 52 . Such factors, which are expressed during inflammation, include the carbohydrate-binding protein galectin-8 53 and interleukin-17 (IL-17) 50 , and contribute to corneal lymphangiogenesis through lymphatic endothelial cell sprouting and proliferation, respectively. Additional factors involved in overcoming immune privilege in the cornea have been reviewed elsewhere 54 .…”