Exogeneous Thrombospondin 1 Inhibits Inflammatory Corneal Lymphangiogenesis in-vivo

Abstract

Purpose: : Lymphangiogenesis, i.e. the outgrowth of new from preexisting lymph vessels, is an important early step in tumor metastasis and transplant host sensitization. We have recently demonstrated, that TSP-1 maintains the lymphangiogenic privilege of the cornea. Aim of this study was to elucidate the molecular mechanism of the antilymphangiogenic effect of TSP-1 and to assess the therapeutic potential of TSP-1 as topical, antilymphangiogenic drug at the ocular surface.

Methods: : We used murine peritoneal exudate cell (PEC) cultures from CD36^-/- and WT mice for real time PCR and protein ELISAs. To test the antilymphangiogenic effect of thrombospondin in-vivo we used the mouse model of inflammation-induced corneal neovascularization and rhTSP-1.

Results: : TSP-1 down regulates the VEGF-C expression in macrophages via the receptor CD36. Thereby TSP-1 antagonises the prolymphangiogenic effect of activated TGFβ. In TSP-1^-/- mice the absence of the VEGF-C homeostatsis in corneal macrophages leads to VEGF-C accumulation and successively to an increase of corneal macrophages which leads to spontaneous lymphangiogenesis in TSP-1 KO mice not only in the cornea but also in e.g. the skin. Functionally, we could significantly reduce the lymphangiogenesis in inflamed corneas using rhTSP-1 as eye drops.

Conclusions: : TSP-1 is an endogenous inhibitor of (inflammation-induced) lymphangiogenesis via the ligation of CD36 on bone-marrow derived monocytic cells. The topical use of rhTSP-1 as an antilymphangiogenic drug could be beneficial for corneal transplantation by hampering the invasion of macrophages and reducing the ingrowth of antigen transporting lymphatic vessels.

Keywords: cornea: basic science • neovascularization • inflammation