A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-κB signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20–deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-κB activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies.

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We are grateful to I. Förster for donating the LysM-Cre transgenic mice. We thank H. Heremans for providing us with the IL-6 and control antibodies. We thank T. Hochepied for transgenic services, P. Bogaert and E. Parthoens for technical help, A. Bredan for critical reading of the manuscript and D. Huyghebaert and L. Bellen for animal care. L.V. and J.M. are PhD fellows with the Instituut voor Innovatie door Wetenschap en Technologie (IWT), and J.M. is also supported by an Emmanuel van der Schueren award. C.M.G., L.G. and P.J. are PhD fellows with the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO). G.v.L. is supported, as a postdoctoral researcher, by the FWO, by an FWO Odysseus Grant and by the Charcot Foundation. M.K. is supported by an Intra European fellowship from the Marie Curie Actions. M.P. is supported by an FP7 EC program grant Masterswitch (EC-223404). B.N.L. is supported by an FWO Odysseus grant, a European Research Council Starting grant and the Group-ID Multidisciplinary Research Partnership grant of Ghent University. Work in the lab of R.B. and G.v.L. is further supported by research grants from the Interuniversity Attraction Poles program (IAP6/18), the FWO, the Belgian Foundation against Cancer, the Strategic Basis Research program of the IWT, the Centrum voor Gezwelziekten, the Hercules Foundation, and the Concerted Research Actions (GOA) and Group-ID MRP of Ghent University.

Author information

Author notes

    • Mourad Matmati
    •  & Peggy Jacques

    These authors contributed equally to this work.

    • Dirk Elewaut
    • , Rudi Beyaert
    •  & Geert van Loo

    These authors jointly directed this work.


  1. Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium.

    • Mourad Matmati
    • , Jonathan Maelfait
    • , Mirjam Kool
    • , Mozes Sze
    • , Conor Mc Guire
    • , Lars Vereecke
    • , Rudi Beyaert
    •  & Geert van Loo
  2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.

    • Mourad Matmati
    • , Jonathan Maelfait
    • , Mozes Sze
    • , Conor Mc Guire
    • , Lars Vereecke
    • , Rudi Beyaert
    •  & Geert van Loo
  3. Department of Rheumatology, Laboratory for Molecular Immunology and Inflammation, Ghent University Hospital, Ghent, Belgium.

    • Peggy Jacques
    • , Eveline Verheugen
    • , Els Louagie
    •  & Dirk Elewaut
  4. Department of Respiratory Diseases, Laboratory of Immunoregulation and Mucosal Immunology, Ghent University Hospital, Ghent, Belgium.

    • Mirjam Kool
    •  & Bart N Lambrecht
  5. Rega Institute, Leuven University, Leuven, Belgium.

    • Lies Geboes
    •  & Patrick Matthys
  6. Max Planck Institute of Biochemistry, Martinsried, Germany.

    • Yuanyuan Chu
    •  & Marc Schmidt-Supprian
  7. Bioceros, Utrecht, The Netherlands.

    • Louis Boon
  8. Medical Image and Signal Processing, Ghent University and Institute for Broadband Technology, Ghent, Belgium.

    • Steven Staelens
  9. Molecular Imaging Center Antwerp, Antwerp University, Antwerp, Belgium.

    • Steven Staelens
  10. Institute for Genetics, Centre for Molecular Medicine (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

    • Manolis Pasparakis


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M.M., P.J., J.M., E.V., M.K., M.S., L.G., E.L., C.M.G., L.V., S.S. and G.v.L. performed the experiments. M.M., P.J., C.M.G., S.S., P.M., B.N.L., M.P., D.E., R.B. and G.v.L. analyzed the data. Y.C., L.B., P.M., M.S.-S. and M.P. provided materials. D.E., R.B. and G.v.L. provided ideas and coordinated the project. R.B. and G.v.L. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Rudi Beyaert or Geert van Loo.

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