Inflammatory lymphangiogenesis plays a crucial role in the development of inflammation and transplant rejection. The mechanisms of inflammatory lymphangiogenesis during bacterial infection, toll-like receptor ligand administration, and wound healing are well characterized and depend on ligands for the vascular endothelial grow factor receptor (VEGFR) 3 that are produced by infiltrating macrophages. But inflammatory lymphangiogenesis in nonlymphoid tissues during chronic viral infection is unstudied. Herpes simplex virus 1 (HSV-1) infection of the cornea is a leading cause of blindness and depends on aberrant host immune responses to antigen within the normally immunologically privileged cornea. We report that corneal HSV-1 infection drives lymphangiogenesis and that corneal lymphatics persist past the resolution of infection. The mechanism of HSV-1–induced lymphangiogenesis was distinct from the described mechanisms of inflammatory lymphangiogenesis. HSV-1–elicited lymphangiogenesis was strictly dependent on VEGF-A/VEGFR-2 signaling but not on VEGFR-3 ligands. Macrophages played no role in the induction of lymphangiogenesis and were not a detectable source of VEGF-A. Rather, using VEGF-A reporter transgenic mice, we have identified infected epithelial cells as the primary source of VEGF-A during HSV-1 infection. Our results indicate that HSV-1 directly induces vascularization of the cornea through up-regulation of VEGF-A expression. Footnotes Abbreviations used: cDNA complementary DNA gC glycoprotein C HSK herpes simplex keratitis HSV-1 herpes simplex virus 1 PI post infection THCE tert-immortalized human corneal epithelial cell TLR Toll-like receptor VEGF vascular endothelial growth factor VEGFR VEGF receptor VSV vesicular stomatitis virus Submitted: 25 June 2009 Accepted: 25 November 2009
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VEGF-A expression by HSV-1–infected cells drives corneal lymphangiogenesis
Wuest, Todd R.; Carr, Daniel J.J.
Follow The Journal of Experimental Medicine
, Volume 207 (1): 101
Rockefeller University Press – Jan 18, 2010
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