The circadian clock regulates inflammatory arthritis

Abstract

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.

The importance of determining circadian parameters in pharmacological studies

“…Tamai et al () screened over 1,000 molecules from a Food and Drug Administration‐approved drug library and found that 5% had effects on the circadian clocks of human osteosarcoma epithelial cells (U2OS cell line). Disruptions in circadian rhythms have been associated with several disorders, including sleep (Vanselow et al, ), metabolic (Marcheva et al, ), neurodegenerative (Musiek, ), cardiovascular (Chen & Yang, ), autoimmune/inflammatory disorders (Hand et al, ), and cancer (El‐Athman, Fuhr, & Relógio, ). In this context, the circadian clock itself may become a therapeutic target for these disorders, along with other conditions associated with impaired circadian rhythms, namely, age‐related diseases.…”

Immunometabolism: Is it under the eye of the clock?

“…This compound has already been shown to have metabolic effects leading to inhibition of glucagon-induced gluconeogenesis in primary hepatocytes. It has also been demonstrated to have an anti-inflammatory role in fibroblast-like synoviocytes (FLSs), a potential candidate for producing rhythmic inflammatory signals during collagen induced arthritis [149]. KL001 and other clock compounds not only provide a tool for dissection of the molecular clock, but may also aid in the development of circadian based treatment for inflammatory and metabolic diseases [148].…”

A Scoring System to Evaluate the Impact of SNPs in a Path Related Context to Study Behçet’s Disease Aetiology in Japanese Population

“…This pathway controls clock output and rhythmic biological processes. In (Hand et al 2016), disruption of the circadian clock is stated as an aggravating factor associated with a range of human inflammatory diseases. Yu et al (2013) showed the role of circadian clock on Th17 cell differentiation.…”