Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis
Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis
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DOI：
10.1038/nm1248
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发表时间：
2005-06-01
期刊：
影响因子：
82.9
通讯作者：
Peng, SL
中科院分区：
文献类型：
--
作者：
Jonsson, H;Allen, P;Peng, SL
在炎性关节炎如类风湿性关节炎中，同源淋巴细胞长期以来被认为是自身免疫的煽动者，但越来越多的证据表明，先天免疫细胞如中性粒细胞和肥大细胞是绝大多数急性和持续炎症的原因（1-3）;然而，控制它们的分子机制在很大程度上仍然未知。在这里，我们表明，这种炎症需要叉头转录因子Foxo 3a：Foxo 3a缺陷的小鼠对两种模型的嗜酸性炎症，免疫复合物介导的炎性关节炎和巯基乙酸盐诱导的腹膜炎。这反映了需要Foxo 3a通过抑制Fas配体在炎症期间维持嗜中性粒细胞活力;因为Foxo 3a可以结合并抑制Fas 1启动子，Foxo 3a缺陷型嗜中性粒细胞上调Fas配体并响应于TNF-α和IL-1而经历凋亡，并且Fas配体阻断使Foxo 3a缺陷型小鼠对关节炎和腹膜炎敏感。因此，Foxo 3a确保炎症期间中性粒细胞存活，将Foxo 3a鉴定为炎症中的治疗靶标。
In inflammatory arthridities such as rheumatoid arthritis, cognate lymphocytes have long been considered instigators of autoimmunity, but accumulating evidence indicates that innate immune cells such as neutrophils and mast cells are responsible for a vast majority of acute and ongoing inflammation(1-3); however, the molecular mechanisms that govern them remain largely unknown. Here we show that such inflammation requires the forkhead transcription factor Foxo3a: Foxo3a-deficient mice are resistant to two models of neutrophilic inflammation, immune complex - mediated inflammatory arthritis and thioglycollate-induced peritonitis. This reflects a need for Foxo3a to maintain neutrophil vitality during inflammation by suppressing Fas ligand; because Foxo3a can bind and suppress the Fasl promoter, Foxo3a-deficient neutrophils upregulate Fas ligand and undergo apoptosis in response to TNF-alpha and IL-1, and Fas ligand blockade renders Foxo3a-deficient mice susceptible to both arthritis and peritonitis. Thus, Foxo3a ensures neutrophil survival during inflammation, identifying Foxo3a as therapeutic target in inflammation.