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- Title
A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis.
- Authors
Matmati, Mourad; Jacques, Peggy; Maelfait, Jonathan; Verheugen, Eveline; Kool, Mirjam; Sze, Mozes; Geboes, Lies; Louagie, Els; McGuire, Conor; Vereecke, Lars; Chu, Yuanyuan; Boon, Louis; Staelens, Steven; Matthys, Patrick; Lambrecht, Bart N.; Schmidt-Supprian, Marc; Pasparakis, Manolis; Elewaut, Dirk; Beyaert, Rudi; van Loo, Geert
- Abstract
A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-?B 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-?B 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.
- Subjects
RHEUMATOID arthritis; LABORATORY mice; TUMOR necrosis factors; NF-kappa B; GENE expression; CACHEXIA
- Publication
Nature Genetics, 2011, Vol 43, Issue 9, p908
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.874