Figure 10
Schematic of HSV-1-induced corneal neovascularization. (a) Naive (uninfected) cornea exhibits basal level of VEGF-A, which is normally neutralized by soluble form of VEGFR-1 present within the cornea. Resident APCs (such as macrophages) decorate the posterior half of the corneal stroma. Limbal vasculature including blood and lymphatic vessels do not penetrate the center cornea under normal conditions. (b) Following HSV-1 infection, VEGF-A is predominantly produced by the infected corneal epithelial cells that drive corneal neovascularization. When the virus is still present in the corneal epithelium, immune cells including PMN, inflammatory monocytes, macrophages, T cells, and NK cells infiltrate the cornea. Various cytokines and growth factors such as IL-6, MMP-9, FGF-2, Ang-2, and HGF are also produced within the cornea leading to further inflammation. (c) When the virus is cleared in the cornea, the immune cells continue to infiltrate, pro-angiogenic factors continue to be produced, and neovascularization prolongs/sustains. However, immune cells do not have a major contribution to corneal neovascularization. MMP-9 is dispensable, IL-6 is necessary but not sufficient, whereas FGF-2 is crucial for HSV-1-induced corneal neovascularization. Importantly, FGF-2 controls the expression of VEGF-A, IL-6, Ang-2, HGF, and MMP-9. The primary source of FGF-2 may not be leukocytes. Instead, resident non-hematopoietic cells of the cornea including fibroblast (keratocytes), epithelium, endothelium, blood endothelial cells (BEC), and lymphatic endothelial cells (LEC) might play important roles in such processes.
