Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages
Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages
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DOI：
10.1038/nature05245
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发表时间：
2006-10-26
期刊：
影响因子：
64.8
通讯作者：
Nagata, Shigekazu
中科院分区：
文献类型：
--
作者：
Kawane, Kohki;Ohtani, Mayumi;Nagata, Shigekazu
大量染色体 DNA 在程序性细胞死亡和确定性红细胞生成过程中被降解 (1)。 DNase II 是一种酶，可消化凋亡细胞和巨噬细胞吞噬红系前体细胞后排出的细胞核的染色体 DNA(1,2)。在这里，我们发现 DNase II-/- IFN-IR-/- 小鼠和诱导删除 DNase II 基因的小鼠会发展出类似于人类类风湿性关节炎的慢性多关节炎。这些小鼠受影响的关节中一组细胞因子基因被强烈激活，其血清中含有高水平的抗环瓜氨酸肽抗体、类风湿因子和基质金属蛋白酶-3。在发病早期，骨髓中编码肿瘤坏死因子 (TNF)-α 的基因表达上调，施用抗 TNF-α 抗体可预防关节炎的发展。这些结果表明，如果巨噬细胞不能降解来自红系前体细胞和凋亡细胞的哺乳动物DNA，它们就会产生TNF-α，从而激活滑膜细胞产生各种细胞因子，导致慢性多关节炎的发展。
A large amount of chromosomal DNA is degraded during programmed cell death and definitive erythropoiesis(1). DNase II is an enzyme that digests the chromosomal DNA of apoptotic cells and nuclei expelled from erythroid precursor cells after macrophages have engulfed them(1,2). Here we show that DNase II-/- IFN-IR-/- mice and mice with an induced deletion of the DNase II gene develop a chronic polyarthritis resembling human rheumatoid arthritis. A set of cytokine genes was strongly activated in the affected joints of these mice, and their serum contained high levels of anti-cyclic citrullinated peptide antibody, rheumatoid factor and matrix metalloproteinase-3. Early in the pathogenesis, expression of the gene encoding tumour necrosis factor (TNF)-alpha was upregulated in the bone marrow, and administration of anti-TNF-alpha antibody prevented the development of arthritis. These results indicate that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNF-alpha, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.