Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Int J Mol Sci. 2023 Aug 1;24(15):12307. doi: 10.3390/ijms241512307.
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.
类风湿关节炎 (RA) 是疾病严重程度存在昼夜波动的最佳范例之一。患有 RA 的患者在清晨会感到受影响关节僵硬、疼痛和肿胀，这种情况往往会在下午缓解。这主要是由于清晨血液中促炎激素和细胞因子（如褪黑素、TNFα、IL-1 和 IL-6）水平较高，以及抗炎皮质醇水平较低（皮质醇水平在清晨后升高）所致。时间治疗学中，根据治疗药物的时间依赖性给药已证明了 RA 症状的昼夜节律调节具有临床重要性。RA 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、趋化因子和酶来相互刺激、募集其他免疫细胞和破骨细胞，从而发挥核心作用，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与炎症活动之间联系的主要目标之一。各种核心生物钟调节剂的基因敲除实验已经证实，当巨噬细胞受到脂多糖和细菌的刺激时，任何核心生物钟调节剂的破坏都会导致其炎症反应过度或低度激活。尽管这些刺激与 RA 的病因没有直接联系，但这些发现为进一步研究提供了依据，证明了其原理。另一方面，巨噬细胞下游效应器破骨细胞的昼夜节律调节仍未得到充分探索。尽管如此，破骨细胞生成诱导剂（如 TNFα、IL-1 和 IL-6）的昼夜表达以及破骨细胞中生物钟调节剂的基因敲除表型表明，昼夜节律控制破骨细胞活性在 RA 发病机制中的重要性。对受影响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 提供新的局部治疗选择。
