The circadian clock regulates inflammatory arthritis.
The circadian clock regulates inflammatory arthritis.
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DOI：
10.1096/fj.201600353r
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Gibbs JE
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文献类型：
--
作者：
Hand LE;Hopwood TW;Dickson SH;Walker AL;Loudon AS;Ray DW;Bechtold DA;Gibbs JE
慢性炎症性疾病（如类风湿性关节炎）的症状和严重程度存在明显的昼夜变化。此外，生物钟紊乱是与一系列人类炎症性疾病相关的加重因素。为了研究生物钟与炎症性关节炎潜在通路之间的机制联系，给小鼠施用胶原蛋白（或生理盐水作为对照）以诱导关节炎。该处理在四肢内引发了炎症反应，爪子肿胀和炎性细胞因子表达呈现出明显的每日变化。在黑暗阶段，炎症标志物受到显著抑制。进一步的研究表明，发炎的四肢内存在活跃的分子生物钟，并强调驻留的炎症细胞——成纤维样滑膜细胞（FLSs）是节律性炎症信号的一个潜在来源。将小鼠暴露于持续光照下会破坏外周组织中的生物钟，导致局部炎症在夜间失去抑制。最后，结果显示核心生物钟蛋白隐花色素（CRY）1和2抑制FLSs内的炎症，并提供了新的证据表明CRY激活剂在人类细胞中具有抗炎特性。我们得出结论，在慢性炎症条件下，生物钟在黑暗阶段积极抑制炎症通路。这种相互作用作为治疗炎症性疾病的一种治疗途径具有令人兴奋的潜力。——汉德，L.E.，霍普伍德，T.W.，迪克森，S.H.，沃克，A.L.，劳登，A.S.I.，雷，D.W.，贝克托尔德，D.A.，吉布斯，J.E.《生物钟调节炎症性关节炎》
There is strong diurnal variation in the symptoms and severity of chronic inflammatory diseases, such as rheumatoid arthritis. In addition, disruption of the circadian clock is an aggravating factor associated with a range of human inflammatory diseases. To investigate mechanistic links between the biological clock and pathways underlying inflammatory arthritis, mice were administered collagen (or saline as a control) to induce arthritis. The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression. Inflammatory markers were significantly repressed during the dark phase. Further work demonstrated an active molecular clock within the inflamed limbs and highlighted the resident inflammatory cells, fibroblast-like synoviocytes (FLSs), as a potential source of the rhythmic inflammatory signal. Exposure of mice to constant light disrupted the clock in peripheral tissues, causing loss of the nighttime repression of local inflammation. Finally, the results show that the core clock proteins cryptochrome (CRY) 1 and 2 repressed inflammation within the FLSs, and provide novel evidence that a CRY activator has anti-inflammatory properties in human cells. We conclude that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease.—Hand, L. E., Hopwood, T. W., Dickson, S. H., Walker, A. L., Loudon, A. S. I., Ray, D. W., Bechtold, D. A., Gibbs, J. E. The circadian clock regulates inflammatory arthritis.