The circadian clock is a biological timing mechanism that allows organisms to align their physiology with the external daily environment. 24h rhythms are generated within every cell by a transcriptional-translational feedback loop, the cellular clock. It is now evident that the cellular clock operates within the immune system, and this explains how responses to inflammatory stimuli show circadian variation. A prime example of this is the macrophage, which is capable of generating 24h rhythms in vivo, but also ex vivo in the absence of entraining signals. Macrophage responses (pro-inflammatory cytokine release) to inflammatory stimuli are significantly greater if the provocation occurs at dusk compared to dawn. Genetic ablation of the clock, by deletion of bmal1, in macrophages, renders them arrhythmic, and results in loss of this time of day variation in response. The cellular clock transmits timing information through REV-ERB alpha, a nuclear hormone receptor and transcriptional repressor. From this we discovered REV-ERB alpha is a tractable pharmacological target for inflammatory disease.
Other cell types involved in the pathogenesis of inflammatory arthritis are also intrinsically rhythmic, including T cells, dendritic cells and synovial fibroblasts. Indeed, using mouse collagen-induced arthritis we have shown that levels of inflammatory markers within inflamed joints show robust 24h rhythmicity. Transcript levels of il1b and il6 peak at dawn, which is remarkably consistent with clinical observations, showing a rise in circulating levels of cytokines in the early morning. Further analysis revealed that the negative arm of the molecular clock (specifically CRYPTOCHROME) suppresses arthritis during the night. Furthermore, small molecule CRYPTOCHROME activators were found to have anti-inflammatory actions in both murine and human synovial fibroblasts – re-affirming the notion that the circadian clock is a therapeutic target for inflammatory disorders.
Disclosure of Interest None declared