title: The circadian clock regulates inflammatory arthritis.
abstract: There is strong diurnal variation in the symptoms and severity of chronic inflammatory diseases, such as rheumatoid arthritis. In addition, disruption of the circadian clock is an aggravating factor associated with a range of human inflammatory diseases. To investigate mechanistic links between the biological clock and pathways underlying inflammatory arthritis, mice were administered collagen (or saline as a control) to induce arthritis. The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression. Inflammatory markers were significantly repressed during the dark phase. Further work demonstrated an active molecular clock within the inflamed limbs and highlighted the resident inflammatory cells, fibroblast-like synoviocytes (FLSs), as a potential source of the rhythmic inflammatory signal. Exposure of mice to constant light disrupted the clock in peripheral tissues, causing loss of the nighttime repression of local inflammation. Finally, the results show that the core clock proteins cryptochrome (CRY) 1 and 2 repressed inflammation within the FLSs, and provide novel evidence that a CRY activator has anti-inflammatory properties in human cells. We conclude that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease.-Hand, L. E., Hopwood, T. W., Dickson, S. H., Walker, A. L., Loudon, A. S. I., Ray, D. W., Bechtold, D. A., Gibbs, J. E. The circadian clock regulates inflammatory arthritis.
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hand
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Hopwood
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Suzanna H
authors.initials: SH
authors.lastname: Dickson
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Walker
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: Andrew S I
authors.initials: AS
authors.lastname: Loudon
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: David W
authors.initials: DW
authors.lastname: Ray
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Bechtold
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom julie.gibbs@manchester.ac.uk.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Gibbs
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000628:therapy; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D008297:Male; D051379:Mice
chemical_list: D056926:CLOCK Proteins
keywords: cryptochrome; diurnal; fibroblast-like synoviocyte; rheumatoid arthritis