Glucocorticoid-Induced Tumor Necrosis Factor Receptor Family-Related Protein Exacerbates Collagen-Induced Arthritis by Enhancing the Expansion of Th17 Cells

Abstract

Rheumatoid arthritis (RA), a chronic autoimmune form of inflammatory joint disease, progressively af- fects multiple joints with pathological changes in the synovia, cartilage, and bone. Numerous studies have suggested a critical role for glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) in the pathogenesis of autoimmune arthritis by modulating both innate and adaptive immune re- actions, but the underlying mechanisms by which GITR activation promotes arthritic progression re- main largely unclear. In this study, we found that collagen-induced arthritis mice treated with the li- gand of GITR (GITRL) displayed an earlier onset of arthritis with a markedly increased severity of ar- thritic symptoms and joint damage, in which signifi- cantly increased Th17 cells in both spleen and drain- ing lymph nodes were observed. Notably, results showed that a marked expansion of Th17 cells with increased ROR␥t mRNA expression was induced from naïve CD4ⴙ T cells when cultured with GITRL. Consis- tently, normal mice that were treated with GITRL were found to display a substantial expansion of splenic Th17 cells. Furthermore, we detected elevated serum levels of GITRL in patients with RA, which were positively correlated with an increase in interleu-kin-17 production. Taken together, the results from this study have revealed a new function of GITRL in exacerbating autoimmune arthritis via the enhance- ment of the expansion of Th17 cells.