Controlling herpetic stromal keratitis by modulating lymphotoxin-alpha-mediated inflammatory pathways

Microbes Infect. 2013 Sep-Oct;15(10-11):677-87. doi: 10.1016/j.micinf.2013.07.001. Epub 2013 Jul 10.

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.

Keywords: CD4(+) T cells; HSV-1; Lymphotoxin alpha; SK; Th1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / virology
  • Herpesvirus 1, Human / immunology*
  • Keratitis, Herpetic / pathology*
  • Keratitis, Herpetic / virology*
  • Lymphotoxin-alpha / antagonists & inhibitors
  • Lymphotoxin-alpha / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Th1 Cells / immunology

Substances

  • Lymphotoxin-alpha