title: The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines.
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-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.
authors.affiliation: Faculty of Life Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Gibbs
authors.forename: John
authors.initials: J
authors.lastname: Blaikley
authors.forename: Stephen
authors.initials: S
authors.lastname: Beesley
authors.forename: Laura
authors.initials: L
authors.lastname: Matthews
authors.forename: Karen D
authors.initials: KD
authors.lastname: Simpson
authors.forename: Susan H
authors.initials: SH
authors.lastname: Boyce
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Farrow
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Else
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.forename: David W
authors.initials: DW
authors.lastname: Ray
authors.forename: Andrew S I
authors.initials: AS
authors.lastname: Loudon
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D002940:Circadian Rhythm / Q000276:immunology*; D004731:Endotoxins / Q000633:toxicity; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000276:immunology*; D013997:Time Factors
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D004731:Endotoxins; D015850:Interleukin-6; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1