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

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Abstract

Objective

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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).

Methods

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.

Results

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.

Conclusion

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.

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Data availability

No datasets were generated or analysed during the current study.

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Funding

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Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Teresina Laragione, Carolyn Harris & Percio S. Gulko

  2. The Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Bernardo Gindri Dos Santos & Leigh Goedeke

  3. The Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Leigh Goedeke

Authors
  1. Teresina Laragione
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  2. Bernardo Gindri Dos Santos
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  3. Carolyn Harris
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  4. Leigh Goedeke
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  5. Percio S. Gulko
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Contributions

TL, PSG develop the concept of this study. TL, PSG, BGS and LG designed the experiments and work plan. TL, CH, BGS and LG conducted all the experiments and analyzed the data. PSG analyzed the data and prepared the figures and tables. PSG and TL wrote the manuscript. All authors reviewed and approved the manuscript.

Corresponding author

Correspondence to Percio S. Gulko.

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The authors declare no competing interests.

Additional information

Communicated by Jason J. McDougall.

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Supplementary Information

Below is the link to the electronic supplementary material.

11_2025_2134_MOESM1_ESM.tif

Supplemental figure 1. Mitochondrial stress, respiration and ATP production. There was no significant different in mitochondrial stress, respiration and ATP production between DUSP6+/+ and DUSP6-/-.

11_2025_2134_MOESM2_ESM.tif

Supplemental figure 2. qPCR confirmation of selected differentially expressed genes (DEGs). Real-time qPCR analyses using the same samples used in the RNA sequencing analyses was used to confirm selected DEGs. The same direction of the DEG expression observed in the RNA sequencing analyses was observed on qPCR, with Axl and Sdc3 reaching statistical significance (** P<0.005).

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Laragione, T., Dos Santos, B.G., Harris, C. et al. Arthritogenicity of CD11b + Gr1 + myeloid cells is dependent on dual specificity phosphatase 6 (DUSP6). Inflamm. Res. 74, 162 (2025). https://doi.org/10.1007/s00011-025-02134-0

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