Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes

Claus Cursiefen, Kazuichi Maruyama, Felix Bock, Daniel Saban, Zahra Sadrai, Jack Lawler, Reza Dana, Sharmila Masli

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Abstract

Lymphangiogenesis plays an important role in tumor metastasis and transplant outcome. Here, we show that thrombospondin-1 (TSP-1), a multifunctional extracellular matrix protein and naturally occurring inhibitor of angiogenesis inhibits lymphangiogenesis in mice. Compared with wild-type mice, 6-mo-old TSP-1-deficient mice develop increased spontaneous corneal lymphangiogenesis. Similarly, in a model of inflammation-induced corneal neovascularization, young TSP-1-deficient mice develop exacerbated lymphangiogenesis, which can be reversed by topical application of recombinant human TSP-1. Such increased corneal lymphangiogenesis is also detected in mice lacking CD36, a receptor for TSP-1. In these mice, repopulation of corneal macrophages with predominantly WT mice via bone marrow reconstitution ameliorates their prolymphangiogenic phenotype. In vitro, exposure of WT macrophages to TSP-1 suppresses expression of lymphangiogenic factors vascular endothelial growth factor (VEGF)-C and VEGF-D, but not of a primarily hemangiogenic factor VEGF-A. Inhibition of VEGF-C is not detected in the absence or blockade of CD36. These findings suggest that TSP-1, by ligating CD36 on monocytic cells, acts as an endogenous inhibitor of lymphangiogenesis.

Original languageEnglish
Pages (from-to)1083-1092
Number of pages10
JournalJournal of Experimental Medicine
Volume208
Issue number5
DOIs
Publication statusPublished - 2011 May

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Cursiefen, C., Maruyama, K., Bock, F., Saban, D., Sadrai, Z., Lawler, J., Dana, R., & Masli, S. (2011). Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. Journal of Experimental Medicine, 208(5), 1083-1092. https://doi.org/10.1084/jem.20092277