Circadian Regulation of Macrophages and Osteoclasts in Rheumatoid Arthritis.
Circadian Regulation of Macrophages and Osteoclasts in Rheumatoid Arthritis.
复制标题
类风湿关节炎中巨噬细胞和破骨细胞的昼夜节律调控。
DOI：
10.3390/ijms241512307
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发表时间：
2023-08-01
影响因子：
5.6
通讯作者：
Kikyo, Nobuaki
中科院分区：
文献类型：
--
作者：
Kikyo, Nobuaki
风湿性关节炎（RA）是疾病严重程度昼夜节律波动的最好例子之一。类风湿关节炎患者在清晨会出现关节僵硬、疼痛和肿胀，下午症状会逐渐减轻。这主要是由于促炎激素和细胞因子（如褪黑激素、TNFα、IL-1和IL-6）的血液水平在清晨高于下午，以及抗炎皮质醇水平不足（在上午晚些时候升高）。RA症状的昼夜节律调节的临床重要性已经通过时间疗法中治疗剂的时间依赖性递送的有效性来证明。RA中的主要炎症部位是滑膜，其中增加的巨噬细胞、T细胞和滑膜成纤维细胞通过分泌促炎细胞因子、趋化因子和酶以相互刺激、额外的免疫细胞和破骨细胞而发挥中心作用，最终导致软骨和骨侵蚀。在这些核心参与者中，巨噬细胞一直是研究昼夜节律和炎症活动之间联系的主要目标之一。各种核心昼夜节律调节因子的基因敲除实验已经确定，任何核心昼夜节律调节因子的破坏都会导致巨噬细胞在受到脂多糖和细菌攻击时炎症反应的过度活化或低活化。虽然这些刺激与RA病因学没有直接联系，但这些发现通过提供原理证明作为进一步研究的基础。另一方面，破骨细胞（巨噬细胞的下游效应物）的昼夜节律调节仍然未被探索。尽管如此，破骨细胞生成诱导物（如TNFα、IL-1和IL-6）的昼夜节律表达，以及破骨细胞中昼夜节律调节因子的敲除表型提示破骨细胞活性的昼夜节律控制在RA发病机制中的重要性。对受累关节中巨噬细胞和破骨细胞的昼夜节律调节的更详细的机制理解可以为RA增加新的局部治疗选择。
Rheumatoid arthritis (RA) represents one of the best examples of circadian fluctuations in disease severity. Patients with RA experience stiffness, pain, and swelling in afflicted joints in the early morning, which tends to become milder toward the afternoon. This has been primarily explained by the higher blood levels of pro-inflammatory hormones and cytokines, such as melatonin, TNFα, IL-1, and IL-6, in the early morning than in the afternoon as well as insufficient levels of anti-inflammatory cortisol, which rises later in the morning. Clinical importance of the circadian regulation of RA symptoms has been demonstrated by the effectiveness of time-of-day-dependent delivery of therapeutic agents in chronotherapy. The primary inflammatory site in RA is the synovium, where increased macrophages, T cells, and synovial fibroblasts play central roles by secreting pro-inflammatory cytokines, chemokines, and enzymes to stimulate each other, additional immune cells, and osteoclasts, ultimately leading to cartilage and bone erosion. Among these central players, macrophages have been one of the prime targets for the study of the link between circadian rhythms and inflammatory activities. Gene knockout experiments of various core circadian regulators have established that disruption of any core circadian regulators results in hyper- or hypoactivation of inflammatory responses by macrophages when challenged by lipopolysaccharide and bacteria. Although these stimulations are not directly linked to RA etiology, these findings serve as a foundation for further study by providing proof of principle. On the other hand, circadian regulation of osteoclasts, downstream effectors of macrophages, remain under-explored. Nonetheless, circadian expression of the inducers of osteoclastogenesis, such as TNFα, IL-1, and IL-6, as well as the knockout phenotypes of circadian regulators in osteoclasts suggest the significance of the circadian control of osteoclast activity in the pathogenesis of RA. More detailed mechanistic understanding of the circadian regulation of macrophages and osteoclasts in the afflicted joints could add novel local therapeutic options for RA.
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影响因子：
27.4
作者：
Buttgereit F;Mehta D;Kirwan J;Szechinski J;Boers M;Alten RE;Supronik J;Szombati I;Romer U;Witte S;Saag KG
通讯作者：
Saag KG
影响因子：
4.9
作者：
Gibbs JE;Ray DW
通讯作者：
Ray DW
昼夜节律时钟控制脓毒症中的免疫检查点通路
影响因子：
8.8
作者：
Deng W;Zhu S;Zeng L;Liu J;Kang R;Yang M;Cao L;Wang H;Billiar TR;Jiang J;Xie M;Tang D
通讯作者：
Tang D
DOI：
10.1073/pnas.1106750109
发表时间：
2012-01-10
影响因子：
11.1
作者：
Gibbs, Julie E.;Blaikley, John;Loudon, Andrew S. I.
通讯作者：
Loudon, Andrew S. I.
影响因子：
2.9
作者：
Derendorf, Hartmut;Ruebsamen, Klaus;Kirwan, John R.
通讯作者：
Kirwan, John R.