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Published on: November 1, 2015
DUSP6 deletion protects mice and reduces disease severity in autoimmune arthritis
Teresina Laragione1, Carolyn Harris1, Natasha Rice1
1Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Abstract:
Receptor 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.
Insights
Dual specificity phosphatase 6 (DUSP6) promotes arthritis severity. DUSP6 deficiency protects against rheumatoid arthritis by increasing IL-10 and regulatory T cells, suggesting DUSP6 as a novel therapeutic target.
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Receptor tyrosine kinases (RTKs) are crucial in rheumatoid arthritis (RA) pathogenesis.
- The role of dual specificity phosphatase 6 (DUSP6) in arthritis and autoimmunity remains unexplored.
- DUSP6 regulates RTK signaling pathways.
Purpose of the Study:
- To investigate the role of DUSP6 in a mouse model of RA.
- To determine if DUSP6 deficiency impacts arthritis severity and immune cell populations.
Main Methods:
- Utilized the KRN serum-induced arthritis (KSIA) model in DUSP6 knockout (DUSP6-/-) and wild-type mice.
- Assessed arthritis scores, joint damage, and serum cytokine levels (IL-10, IL-6).
- Quantified IL-10+ cells, including Tr1 regulatory cells, and generated double knockout mice (DUSP6-/- IL-10-/-).
Main Results:
- DUSP6-/- mice exhibited significantly reduced arthritis severity (50% lower maximum score) and joint damage compared to controls.
- DUSP6-/- mice showed increased serum IL-10 levels and decreased IL-6 levels.
- A higher number of IL-10+ cells, including Tr1 regulatory cells, were observed in DUSP6-/- mice.
- Deletion of IL-10 in DUSP6-/- mice reversed the protective phenotype, highlighting IL-10's critical role.
Conclusions:
- This study identifies a pro-arthritic role for DUSP6 in the context of RA.
- DUSP6 deficiency confers protection against arthritis, mediated by enhanced IL-10 production and regulatory T cells.
- DUSP6 emerges as a potential novel therapeutic target for RA and other inflammatory diseases.
