Nrf2 activation improves experimental rheumatoid arthritis.

Abstract

Rheumatoid arthritis is a systemic autoimmune disease with pain and functional disorder of joints. Multiple strategies toward treatment of the rheumatoid arthritis are operating, while there are concerns of serious adverse effects of the therapeutic drugs. Here, we show that activation of Nrf2 (Nuclear factor erythroid 2-related factor 2) efficiently improves arthritis of SKG mice, which develop T cell-mediated autoimmune arthritis by zymosan A injection. We found that genetic Nrf2 activation by knockdown of Keap1 (Kelch-like ECH-associated protein 1), a negative regulator of Nrf2, repressed arthritis by inhibiting the expression of pro-inflammatory cytokines and inducing the expression of antioxidant enzymes in SKG mice. In addition, oral administration of CDDO-Im, a representative chemical inducer of Nrf2, had effects of both prevention and treatment toward arthritis of SKG mice in an Nrf2-dependent manner. We also found that Nrf2 activation through myeloid-cell lineage-specific Keap1 disruption did not achieve significant improvement in the arthritis of SKG mice. In contrast, expressions of pro-inflammatory cytokine genes were decreased, and those of antioxidant enzyme genes were increased in fibroblast-like synoviocytes (FLS) isolated from SKG mouse. Our results thus demonstrate that Nrf2 activation exerts marked anti-arthritis effects in the SKG experimental rheumatoid arthritis model mice, supporting the contention that the Nrf2 activation is a new therapeutic strategy for the rheumatoid arthritis.