DUSP6 deletion protects mice and reduces disease severity in autoimmune arthritis

Highlights•DUSP6 is associated with increased disease severity and joint damage in autoimmune arthritis•Mice with a DUSP6 deletion are significantly protected, preserving normal joints•DUSP6 knockout mice exhibit increased serum levels of IL10 and IL10-producing cells but reduced IL6•DUSP6 is a potential therapeutic target for autoimmune and inflammatory diseases such as RASummaryReceptor tyrosine kinases (RTKs) have an important role in arthritis severity and in models of rheumatoid arthritis (RA), but their regulation is not fully understood. The dual specificity phosphatase 6 (DUSP6) has been implicated in the regulation of RTK signaling, but never in the context of arthritis and autoimmunity. We used the KRN serum-induced arthritis (KSIA) model of RA and showed that DUSP6−/− mice were protected and had a 50% lower maximum arthritis score (p = 0.006) and reduced joint damage than C57BL/6 DUSP6+/+ controls. Serum levels of interleukin (IL) 10 were significantly increased (>2-fold), and IL6 decreased in DUSP6−/− mice. DUSP6−/− mice had increased numbers of IL10+ cells including Tr1 regulatory cells (p < 0.01). Introduction of the IL10−/− into DUSP6−/− (double knockout [KO]) reversed the DUSP6−/− protection. In conclusion, this study reports a pro-arthritic role for DUSP6. This discovery has the potential to generate a previously unknown target for therapies for RA and inflammatory diseases.Graphical abstract