A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis
A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis
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DOI：
10.1038/ng.874
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发表时间：
2011-09-01
期刊：
影响因子：
30.8
通讯作者：
van Loo, Geert
中科院分区：
文献类型：
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作者：
Matmati, Mourad;Jacques, Peggy;van Loo, Geert
A20（TNFAIP 3）是一种蛋白质，其参与NF-κ B信号传导的负反馈调节，以响应不同细胞类型中的特异性促炎刺激，并且已被认为是类风湿性关节炎的易感基因。为了确定A20对类风湿性关节炎病理学的贡献，我们产生了骨髓特异性A20缺陷小鼠，并表明骨髓细胞中Tnfaip 3的特异性消融导致自发发展具有许多类风湿性关节炎特征的严重破坏性多发性关节炎。骨髓A20缺陷小鼠血清中有高水平的炎性细胞因子，这与持续的NF-κ B活化和巨噬细胞产生的较高TNF相一致。髓系A20基因敲除小鼠的破坏性多关节炎是TLR 4-MyD 88和IL-6依赖性的，但不依赖于TNF。骨髓A20缺乏也促进小鼠破骨细胞生成。总之，这些观察结果表明A20在类风湿性关节炎的病因学中具有关键的细胞特异性功能，支持开发A20调节药物作为细胞靶向疗法的想法。
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.