Activation of endothelial roundabout receptor 4 reduces the severity of virus-induced keratitis

Antiangiogenic molecules exert a feedback control to restrain pathological angiogenesis, which includes physical binding or inhibition of angiogenic signaling in blood vessel endothelial cells. The latter is the case in which Slit2 ligand-dependent activation of the blood vessel endothelial cell rec...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2011-06, Vol.186 (12), p.7195-7204
Main Authors: Mulik, Sachin, Sharma, Shalini, Suryawanshi, Amol, Veiga-Parga, Tamara, Reddy, Pradeep B J, Rajasagi, Naveen K, Rouse, Barry T
Format: Article
Language:English
Subjects:
Animals
Eye Infections - virology
Female
Herpes Simplex
Keratitis - pathology
Keratitis - virology
Mice
Neovascularization, Pathologic
Nerve Tissue Proteins - metabolism
Protective Agents
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Receptors, Immunologic - metabolism
Simplexvirus
Up-Regulation
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Summary:Antiangiogenic molecules exert a feedback control to restrain pathological angiogenesis, which includes physical binding or inhibition of angiogenic signaling in blood vessel endothelial cells. The latter is the case in which Slit2 ligand-dependent activation of the blood vessel endothelial cell receptor roundabout 4 (Robo4) occurs. In this study, we demonstrate that Robo4 receptors are upregulated following HSV infection of the eye on the majority of the new blood vessel endothelial cells that occur in the corneal stroma. However, expression levels of the ligand for Robo4 receptors, Slit2, was not significantly increased during the disease process, and the knockdown of Slit2 gene expression using lentiviral short hairpin RNAs had no effect on the extent of pathological angiogenesis. In contrast, providing additional Slit2 protein by subconjunctival administration resulted in significantly reduced angiogenesis. The Slit2 binding to Robo4 was shown to block the downstream vascular endothelial growth factor signaling molecules Arf 6 and Rac 1 and reduce the antiapoptotic molecule Bcl-xL in blood vessel endothelial cells. Our results indicate that augmenting the host Robo4/Slit2 system could provide a useful therapeutic approach to control pathological angiogenesis associated with HSV induced stromal keratitis.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1100014