A20 (also known as TNFAIP3) is a potent anti-inflammatory protein that inhibits NF-κB activation in response to multiple cytokine and pattern recognition receptors. In addition, A20 also negatively regulates TNF-induced cell death. Specific signaling proteins are targeted by the deubiquitinating activity of A20, but A20 can also use non-catalytic mechanisms to interfere with NF-κB signaling. Polymorphisms in the A20 genomic locus have been associated with multiple inflammatory and autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, Crohn’s disease and psoriasis. To further analyze the contribution of A20 defects in autoimmunity we generated multiple tissue specific A20 knockout mice. Specific ablation of A20 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Despite higher circulating TNF levels, arthritis development in the myeloid specific A20 deficient mice was TNF-independent. Lessons learned from the phenotype of these mice and a number of other cell type specific A20 deficient mice that we generated will be presented.
Disclosure of Interest None Declared
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