Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, NF-KAPPA-B, ESCHERICHIA-COLI, MICE LACKING, ENZYME A20, RECEPTOR, OSTEOCLASTOGENESIS, PATHOGENESIS, INFLAMMATION, ANTIBODIES, INFECTION, Animals, Arthritis, Rheumatoid, Cysteine Endopeptidases, Cytokines, Intracellular Signaling Peptides and Proteins, Macrophages, Mice, Mice, Knockout, Myeloid Cells, NF-kappa B, Tumor Necrosis Factor alpha-Induced Protein 3, Tumor Necrosis Factor-alpha, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3001 Agricultural biotechnology, 3102 Bioinformatics and computational biology, 3105 Genetics

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.