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

Salvatore Cuzzocrea^*,1, Emira Ayroldi^,1, Rosanna Di Paola^*, Massimiliano Agostini, Emanuela Mazzon^*, Stefano Bruscoli, Tiziana Genovese^*, Simona Ronchetti, Achille P. Caputi^* and Carlo Riccardi^,1

^* Dipartimento Clinico e Sperimentale di Medicina e Farmacologia, Torre Biologica, Policlinico Universitario, Messina, Italy; and
Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Tossicologia e Chemioterapia, Università di Perugia, Perugia, Italy

²Correspondence: C. R., E-mail: riccardi{at}unipg.it and S.C., Dipartimento Clinico e Sperimentale di Medicina e Farmacologia, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy. E-mail: salvator{at}unime.it

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 IFN, IL-6, TNF, MIP-1, 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.—Cuzzocrea, S., Ayroldi, E., Di Paola, R., Agostini, M., Mazzon, E., Bruscoli, S., Genovese, T., Ronchetti, S., Caputi, A. P., Riccardi, C. Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis.

Key Words: rheumatoid arthritis • T lymphocyte activity • chemokines

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