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

TLDR

Diurnal variation in inflammatory and immune function is observed in humans and animals, yet the molecular mechanisms and cell types that gate this rhythm remain unknown. By comparing endotoxin‑induced cytokine responses at different times of day, the authors showed that only certain pro‑inflammatory cytokines exhibit temporal gating, which is abolished when the macrophage clock gene Bmal1 is disrupted or when REV‑ERBα activity is genetically or pharmacologically modulated, demonstrating that REV‑ERBα mediates this circadian regulation. Loss of REV‑ERBα eliminates circadian gating of endotoxin responses in mice and macrophages while preserving intrinsic circadian rhythms, establishing REV‑ERBα as a key link between the clock and innate immunity and suggesting it as a potential therapeutic target for inflammatory disease.

Abstract

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-erb α 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-ERB α activity. Circadian gating of endotoxin response was lost in rev-erb α −/− 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-erb α 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.