Hand Laura E, Hopwood Thomas W, Dickson Suzanna H, Walker Amy L, Loudon Andrew S I, Ray David W, Bechtold David A, Gibbs Julie E
Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom
FASEB J. 2016 Nov;30(11):3759-3770. doi: 10.1096/fj.201600353R. Epub 2016 Aug 3.
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.
慢性炎症性疾病，如类风湿性关节炎，其症状和严重程度存在强烈的昼夜变化。此外，生物钟的紊乱是一系列人类炎症性疾病的一个加重因素。为了研究生物钟与炎性关节炎潜在机制之间的联系，给小鼠注射胶原蛋白（或生理盐水作为对照）以诱发关节炎。这种处理引发了四肢的炎症反应，表现为爪肿胀和炎性细胞因子表达呈现出明显的每日变化。炎症标志物在黑暗期显著受到抑制。进一步的研究表明，在发炎的四肢中存在活跃的分子生物钟，并突出了驻留的炎症细胞，即成纤维样滑膜细胞（FLS），作为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扰乱外周组织中的生物钟，导致局部炎症夜间抑制作用的丧失。最后，结果表明核心生物钟蛋白隐花色素（CRY）1和2在FLS中抑制炎症，并提供了新的证据，即一种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，生物钟在黑暗期积极抑制炎症途径。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. 生物钟调节炎性关节炎。
