The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines

Dec 21, 2011Proceedings of the National Academy of Sciences of the United States of America

The receptor REV-ERBα controls daily rhythms in innate immunity by selectively regulating inflammatory signals

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Abstract

Disruption of the circadian clock in macrophages eliminates temporal regulation of endotoxin-induced cytokine response.

Cytokine responses in mice to endotoxin vary significantly depending on the time of day.
Only a subset of proinflammatory cytokines exhibited this pronounced temporal dependence.
Conditional targeting of the bmal1 gene disrupted circadian rhythms and abolished temporal gating of cytokine response in macrophages.
Loss of circadian gating correlated with decreased expression of rev-erbα, suggesting its role in linking circadian rhythms to inflammation.
In rev-erbα(-/-) mice and in cultured macrophages from these mice, circadian gating of endotoxin response was lost, despite maintained circadian rhythms.
In human macrophages, modulation of REV-ERBα activity influenced the production and release of the proinflammatory cytokine IL-6.

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Diurnal variation in inflammatory and immune function is evident in the physiology and pathology of humans and animals, but molecular mechanisms and mediating cell types that provide this gating remain unknown. By screening cytokine responses in mice to endotoxin challenge at different times of day, we reveal that the magnitude of response exhibited pronounced temporal dependence, yet only within a subset of proinflammatory cytokines. Disruption of the circadian clockwork in macrophages (primary effector cells of the innate immune system) by conditional targeting of a key clock gene (bmal1) removed all temporal gating of endotoxin-induced cytokine response in cultured cells and in vivo. Loss of circadian gating was coincident with suppressed rev-erbα expression, implicating this nuclear receptor as a potential link between the clock and inflammatory pathways. This finding was confirmed in vivo and in vitro through genetic and pharmacological modulation of REV-ERBα activity. Circadian gating of endotoxin response was lost in rev-erbα(-/-) mice and in cultured macrophages from these animals, despite maintenance of circadian rhythmicity within these cells. Using human macrophages, which show circadian clock gene oscillations and rhythmic endotoxin responses, we demonstrate that administration of a synthetic REV-ERB ligand, or genetic knockdown of rev-erbα expression, is effective at modulating the production and release of the proinflammatory cytokine IL-6. This work demonstrates that the macrophage clockwork provides temporal gating of systemic responses to endotoxin, and identifies REV-ERBα as the key link between the clock and immune function. REV-ERBα may therefore represent a unique therapeutic target in human inflammatory disease.

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The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines

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