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

Chen, Wei Sheng; Cao, Zhiyi; Sugaya, Satoshi; Lopez, Maria J.; Sendra, Victor G.; Laver, Nora; Leffler, Hakon LU ; Nilsson, Ulf J. LU ; Fu, Jianxin and Song, Jianhua, et al. (2016) In Nature Communications 7.
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... (More)

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.

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Nature Communications
volume
7
publisher
Nature Publishing Group
external identifiers
  • Scopus:84964319308
  • WOS:000373832000001
ISSN
2041-1723
DOI
10.1038/ncomms11302
language
English
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yes
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b25ed55f-e79f-4605-9903-47b6c9013158
date added to LUP
2016-10-03 09:55:07
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2017-01-22 04:32:48
@article{b25ed55f-e79f-4605-9903-47b6c9013158,
  abstract     = {<p>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 <sup>-/-</sup> and Pdpn <sup>-/-</sup> mice; likewise, galectin-8-induced lymphangiogenesis is reduced in Pdpn <sup>-/-</sup> 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.</p>},
  articleno    = {11302},
  author       = {Chen, Wei Sheng and Cao, Zhiyi and Sugaya, Satoshi and Lopez, Maria J. and Sendra, Victor G. and Laver, Nora and Leffler, Hakon and Nilsson, Ulf J. and Fu, Jianxin and Song, Jianhua and Xia, Lijun and Hamrah, Pedram and Panjwani, Noorjahan},
  issn         = {2041-1723},
  language     = {eng},
  month        = {04},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3},
  url          = {http://dx.doi.org/10.1038/ncomms11302},
  volume       = {7},
  year         = {2016},
}