Dual-specificity phosphatase 5 attenuates autoimmune arthritis in mice via reciprocal regulation of the Th17/Treg cell balance and inhibition of osteoclastogenesis.

Abstract

Dual-specificity phosphatase 5 (DUSP-5) is a phosphatase that specifically dephosphorylates both phosphoserine and phosphotyrosine residues of MAPK. The dysregulated activation of MAPK contributes to the pathogenesis of rheumatoid arthritis. This study was undertaken to investigate the therapeutic potential of DUSP-5 in preventing the development of autoimmune arthritis in an animal model. Autoimmune arthritis was induced in DBA/1J mice by immunization with type II collagen (CII). Eight days after CII immunization, the mice were injected intravenously with pcDNA-DUSP5 or mock vector, and electroporation was performed. The serum concentration of anti-CII antibodies was measured by enzyme-linked immunosorbent assay. Histologic analysis of the joints was performed using Safranin O, toluidine blue, and immunohistochemical staining. The expression of transcription factors was analyzed by immunostaining and Western blotting. The frequencies of interleukin-17-producing CD4+ Th17 cells and CD4+CD25+Foxp3+ Treg cells were analyzed by flow cytometry. In DUSP5-overexpressing mice, the severity of arthritis, as indicated by the clinical arthritis score and the extent of histologic inflammation and cartilage damage, was attenuated. The pcDNA-DUSP5-injected mice had lower circulating levels of total and CII-specific IgG, IgG1, and IgG2a. The Th17 cell population frequency was decreased and the Treg cell frequency was increased in the spleens of the DUSP5-treated group. The reciprocal regulation of Th17 and Treg cells in vivo was associated with attenuated activity of pSTAT-3 and pERK, and with increased activity of pSTAT-5. DUSP5 overexpression suppressed joint damage through down-regulation of pro-osteoclastogenic molecules. The antiarthritic properties of DUSP-5 are associated with its reciprocal regulation of Th17 and Treg cells and its inhibition of ERK activity.