A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis

Nat Genet. 2011 Aug 14;43(9):908-12. doi: 10.1038/ng.874.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / pathology*
  • Cysteine Endopeptidases / genetics*
  • Cytokines / blood
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Myeloid Cells / enzymology*
  • NF-kappa B / metabolism
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Cysteine Endopeptidases
  • Tnfaip3 protein, mouse