title: IL-17A differentially regulates corneal vascular endothelial growth factor (VEGF)-A and soluble VEGF receptor 1 expression and promotes corneal angiogenesis after herpes simplex virus infection.
abstract: Ocular infection with HSV causes corneal neovascularization (CV), an essential step in the pathogenesis of the blinding immunoinflammatory lesion stromal keratitis. The infection results in IL-17A production, which contributes to CV in ways that together serve to shift the balance between corneal concentrations of vascular endothelial growth factor A (VEGF-A) and the soluble vascular endothelial growth factor receptor 1 molecule, which binds to VEGF-A and blocks its function (a so-called VEGF trap). Accordingly, animals lacking responses to IL-17A signaling, either because of IL-17 receptor A knockout or wild-type animals that received neutralizing mAb to IL-17A, had diminished CV, compared with controls. The procedures reduced VEGF-A protein levels but had no effect on the levels of soluble vascular endothelial growth factor receptor 1. Hence the VEGF trap was strengthened. IL-17A also caused increased CXCL1/KC synthesis, which attracts neutrophils to the inflammatory site. Neutrophils further influenced the extent of CV by acting as an additional source of VEGF-A, as did metalloproteinase enzymes that degrade the soluble receptor, inhibiting its VEGF-blocking activity. Our results indicate that suppressing the expression of IL-17A, or increasing the activity of the VEGF trap, represents a useful approach to inhibiting CV and the control of an ocular lesion that is an important cause of human blindness.
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996-0854, USA. amsuryawanshi@emory.edu
authors.forename: Amol
authors.initials: A
authors.lastname: Suryawanshi
authors.forename: Tamara
authors.initials: T
authors.lastname: Veiga-Parga
authors.forename: Pradeep B J
authors.initials: PB
authors.lastname: Reddy
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Rajasagi
authors.forename: Barry T
authors.initials: BT
authors.lastname: Rouse
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D003315:Cornea / Q000378:metabolism; D016510:Corneal Neovascularization / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016849:Keratitis, Herpetic / Q000150:complications*; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D016207:Cytokines; C098680:Il17a protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D020782:Matrix Metalloproteinases