Metallothionein‐1 suppresses rheumatoid arthritis pathogenesis by shifting the Th17/Treg balance

It is now well accepted that an imbalance between the Th17 and regulatory T‐cell responses is closely associated with the development of rheumatoid arthritis (RA). However, the precise regulatory mechanism for the differentiation of Th17 and Treg in RA is not well characterized. The present study showed that metallothionein‐1 (MT‐1), which is a low molecular weight protein that is involved in the detoxification of heavy metals and scavenging of free radicals, was upregulated in RA. Furthermore, the synovial inflammation and pathologic symptoms in collagen‐induced arthritis and collagen antibody‐induced arthritis mice were significantly suppressed when MT‐1 was expressed intraarticularly. Further investigation revealed that MT‐1 inhibited the differentiation of Th17 cells but enhanced that of Treg cells. Furthermore, it markedly decreased both STAT3 and RAR‐related orphan receptor gamma t (RORγt) expression in vitro and in vivo. Collectively, our studies demonstrated that MT‐1 might manifest as a protein involved in immunosuppression of RA pathogenesis by shifting Th17/Treg balance and may prove to be a potential therapeutic target for RA autoimmune diseases. This indicates a negative feedforward mechanism for MT‐1 in RA immunoregulation. RA inflammation can upregulates MT‐1 expression. Furthermore, MT‐1 in turn inhibits proinflammatory cytokines expression and shifts the balance of Th17/Treg, thereby inhibiting the RA immune inflammation.