Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis

Salvatore Cuzzocrea, Emira Ayroldi, Rosanna Di Paola, Massimiliano Agostini, Emanuela Mazzon, Stefano Bruscoli, Tiziana Genovese, Simona Ronchetti, Achme P. Caputi, Carlo Riccardi

Research output: Contribution to journalArticlepeer-review

Abstract

In rheumatoid arthritis (RA), a widespread autoimmune/inflammatory joint disease, early activation of effector CD4+ T lymphocytes, and cytokine production is followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, and disease. GITR (glucocorticoid-induced TNFR family-related gene), a costimulatory molecule for T lymphocytes, increases CD4+CD25- effector T cell activation while inhibiting suppressor activity of CD4+CD25+ T regulatory (Treg) cells. We analyzed the role of GITR in type II collagen (CII) -induced arthritis (CIA) using GITR-/-and GITR+/+ mice. Results indicate significantly less CIA induction in GITR-/- mice than in GITR+/+ mice, with marked differences in erythema, edema, neutrophil infiltration, joint injury, and bone erosion. Production of IFNγ, IL-6, TNFα, MIP-1α, and MIP-2, inducible NOS (iNOS), COX-2, and nitrotyrosine poly-ADP-ribose (PAR) were also less in CII-treated GITR-/- mice. Although CD4+CD25+ Treg cells from GITR+/+ and GITR-/- CII-challenged mice exerted similar suppressor activity in vitro, GITR triggering abrogated GITR+/+ Treg suppressor activity and costimulated CD4+CD25- GITR+/+ effector cells. Furthermore, Treg cells from GITR-/- protected more than Treg cells from GITR+/+ mice against CIA when cotransferred with Treg-depleted splenocytes from arthritic GITR+/+ animals into severe combined immunodeficient (SCID) mice. In conclusion, GITR plays a critical role in the immunological response against CII and in the development of CIA.

Original languageEnglish
Pages (from-to)1253-1265
Number of pages13
JournalFASEB Journal
Volume19
Issue number10
DOIs
Publication statusPublished - Aug 2005

Keywords

  • Chemokines
  • Rheumatoid arthritis
  • T lymphocyte activity

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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