期刊
NATURE GENETICS
卷 43, 期 9, 页码 908-U129出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.874
关键词
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资金
- Emmanuel van der Schueren award
- FWO
- Charcot Foundation
- Marie Curie Actions
- EC [EC-223404]
- European Research Council
- Ghent University
- Interuniversity Attraction Poles program [IAP6/18]
- Belgian Foundation against Cancer
- IWT
- Centrum voor Gezwelziekten
- Hercules Foundation
- Concerted Research Actions (GOA)
- Group-ID MRP of Ghent University
A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-kappa 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-kappa 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.
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