Matmati, Mourad × Jacques, Peggy Maelfait, Jonathan Verheugen, Eveline Kool, Mirjam Sze, Mozes Geboes, Lies Louagie, Els Guire, Conor Mc 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 #
Nature Publishing Group
Nature Genetics vol:43 issue:9 pages:908-12
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.