Dendritic cell-derived thrombospondin-1 is critical for the generation of the ocular surface Th17 response to desiccating stress

J Leukoc Biol. 2013 Dec;94(6):1293-301. doi: 10.1189/jlb.1012524. Epub 2013 Aug 27.

Abstract

TSP-1 is a physiologic activator of TGF-β, a critical induction factor for Th17-mediated immunity. The purpose of this study was to investigate the role of TSP-1 in the induction of the Th17 ocular surface response to DS. TSP-1KO and WT mice were subjected to DS5 and DS10), and parameters of ocular surface disease, including corneal barrier function, conjunctival CD4(+) T cell infiltration, and GC density, were evaluated. TSP-1KO mice subjected to DS had less corneal barrier disruption, reduced loss of PAS+ GC, and decreased CD4(+) T cell infiltration in the conjunctiva. In contrast to WT, TSP-1KO mice failed to up-regulate MMP-3 and MMP-9 mRNA transcripts in the cornea and IL-17A mRNA transcripts in the conjunctiva. RAG-1KO recipients of adoptively transferred CD4(+) T cells isolated from TSP-1KO mice subjected to DS5 showed milder dry-eye phenotype and less conjunctival inflammation than recipients of CD4(+) T cells from DS5 WT control. Reconstitution of TSP-1KO mice with WT DCs prior to DS reversed the resistance of the TSP-1KO to DS-induced immunopathology. In conclusion, DC-derived TSP-1 is critical for generating the Th17 ocular surface response to DS.

Keywords: IFN-γ; IL-17A; TGF-β; conjunctiva; corneal permeability; dry eye; goblet cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Conjunctiva / immunology
  • Conjunctiva / metabolism
  • Conjunctiva / pathology
  • Cornea / immunology
  • Cornea / metabolism
  • Cornea / pathology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Dry Eye Syndromes / genetics
  • Dry Eye Syndromes / immunology*
  • Dry Eye Syndromes / pathology
  • Eye Proteins / genetics
  • Eye Proteins / immunology*
  • Eye Proteins / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Stress, Physiological / genetics
  • Stress, Physiological / immunology*
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism
  • Th17 Cells / pathology
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / immunology*
  • Thrombospondin 1 / metabolism
  • Time Factors
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism

Substances

  • Eye Proteins
  • Thrombospondin 1
  • Transforming Growth Factor beta
  • thrombospondin-1, mouse