Arthritogenicity of CD11b + Gr1 + myeloid cells is dependent on dual specificity phosphatase 6 (DUSP6)

The dual specificity phosphatase 6 (DUSP6) was recently implicated in autoimmune arthritis pathogenesis. However, it remains unclear which cell mediates its pathogenic activity in a mouse model of rheumatoid arthritis (RA).

Bone marrow (BM) CD11b + Gr1 + cells were isolated from DUSP6 +/+ mice and transferred into DUSP6 -/- recipients. Six weeks later mice were administered the KRN serum to induce arthritis (KSIA), and analyzed for arthritis severity clinical scores. The same strategy was used in the opposite direction with cells from DUSP6-/- cells transferred in DUSP6 +/+ mice. BM CD11b + Gr1 + cells from DUSP6 +/+ and DUSP6 -/ - were stimulated with PMA and used for RNA sequencing, and also used for real-time measurements of mitochondrial respiration with the Seahorse XF Analyzer.

Transfer of CD11 + Gr1 + cells DUSP6^+/+ mice into DUSP6^-/- mice reversed the arthritis protection observed in the knockout mice, and developed severe disease. Transfer of cells from DUSP6^-/- into DUSP6^+/+ were not protective and mice still developed severe disease. Cells from DUSP6 +/+ mice had a significantly higher oxidative burst, and higher glycolysis, compared with reduced levels in DUSP6-/-. RNA sequencing analyses revealed an enrichment for differentially expressed genes implicated in RA, MAPK signaling, leukocyte differentiation and neutrophil degranulation, among others.

We describe a new arthritogenic role for DUSP6, which is mediated by CD11b + Gr1 + cells and their glycolytic activity and oxidative burst. Our findings also implicate these myeloid cells in arthritis pathogenesis and raise the possibility that DUSP6 may be a good target for the development of new therapies for RA.