title: Controlling herpetic stromal keratitis by modulating lymphotoxin-alpha-mediated inflammatory pathways.
abstract: Herpes simplex virus 1 infection of the eye can result in stromal keratitis, a chronic immunoinflammatory lesion that is a significant cause of human blindness. A key to controlling the severity of lesions is to identify cellular and molecular events responsible for tissue damage. This report evaluates the role of lymphotoxin-α, a proinflammatory cytokine that could be involved during stromal keratitis. We demonstrate that after infection, both lymphotoxin-α and lymphotoxin-β transcripts are detectable at high levels 48 h postinfection, suggesting roles for the secreted homotrimer lymphotoxin-α3 and the membrane-bound lymphotoxin-α1β2 heterotrimer in stromal keratitis. Using a corneal stromal fibroblast cell line, lymphotoxin-α3 and lymphotoxin-α1β2 were found to have proinflammatory roles by stimulating production of chemokines. Treatment of mice with a depleting anti-lymphotoxin-α mAb during the clinical phase of the disease significantly attenuated stromal keratitis lesions. In treated mice, expression of proinflammatory molecules and chemokines was reduced, as were numbers of cornea-infiltrating proinflammatory cells, particularly Th1 cells. The protective effect of anti-lymphotoxin-α mAb was highly reduced with a mutant version of the mAb that lacks Fc receptor binding activity, indicating that depletion of lymphotoxin-expressing cells was mainly responsible for efficacy, with LT-α3 contributing minimally to inflammation. These data demonstrate that lymphotoxin-expressing cells, such as Th1 cells, mediate stromal keratitis.
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 1414 Cumberland Avenue, Rm. F403, Knoxville, TN 37996, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Veiga-Parga
authors.forename: Fernanda
authors.initials: F
authors.lastname: Giménez
authors.forename: Sachin
authors.initials: S
authors.lastname: Mulik
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Chiang
authors.forename: Jane L
authors.initials: JL
authors.lastname: Grogan
authors.forename: Barry T
authors.initials: BT
authors.lastname: Rouse
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D016849:Keratitis, Herpetic / Q000473:pathology* / Q000821:virology*; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000276:immunology
chemical_list: D008233:Lymphotoxin-alpha
keywords: CD4(+) T cells; HSV-1; Lymphotoxin alpha; SK; Th1