We live in a world that rotates, giving us day and night. In response to this oscillating environment circadian clocks have evolved, and are now recognised to regulate many metabolic, and immune circuits. The central circadian clock lies in the brain, and received light input signals to keep in time to the external world. Excitingly, it is now clear that all peripheral cells and tissues also have clocks, which are synchronised to the central clock by neural, and humoral signals.
Inflammatory signals including cytokines, prostaglandins, and temperature all regulate expression and function of circadian clock components, resulting in advancing, or delaying the clock phase. However, it has also recently emerged that the circadian clock operating within immune cells drives inflammatory response. We discovered that the circadian clock in murine macrophages drives distinct inflammatory responses both in-vivo and in vitro. We disrupted the clock in macrophages, which abolished the circadian nadir in inflammatory response, thereby de-repressing inflammation. In primary human peripheral blood mononuclear cells we also found marked circadian gating of inflammatory response.
In murine adjuvant induced arthritis joint swelling, and circulating pro-inflammatory cytokines exhibit a circadian variation, with nadir at night. Moreover, analysis of joint tissue revealed circadian oscillation in inflammatory gene expression. Strikingly, phase-shifting animals resulted in a phase shift in arthritis expression, and disruption of circadian rhythms by constant light abolished the variation in arthritis expression. These results suggested that a component of the circadian inflammation in rheumatoid arthritis may be driven by the immune system intrinsic circadian clock. To investigate this we recruited patients with RA, and studied their circulating PBMLs at dawn and dusk. These studies revealed a marked time of day control of p38SAPK activity, both in healthy volunteers, and RA; although absolute p38SAPK activation was higher in RA. To investigate the consequences of these observations further we studied activation of target cytokine genes in the same cells. These studies showed that the evening nadir in gene expression response was less marked in RA.
We identified the output pathway from the clock to inflammation as being through the orphan nuclear receptor REVERBa. REVERBa lies under strong circadian control, and is itself a component of the clock feedback mechanism. The natural ligand for REVERB appears to be heme, but we have now identified novel, synthetic small molecule ligands. These suppress expression of IL-6, which has emerged as strongly circadian regulated, and a direct REVERB target gene.
Taken together, our data reveal that aspects of inflammation are directly coupled to the circadian clock operating in immune cells. Moreover, determining how the core clock drives inflammation offers new drug targets, and understanding how clock phase affects inflammation, and drug metabolism may offer the means to enhance the therapeutic effects of existing drugs.
Disclosure of Interest None declared
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