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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 CRYPTOCHROMES 1 and 2 repressed
inflammation within the FLSs, and provide novel
evidence that a CRYPTOCHROME 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.
For more information
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.
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