Abstract
Objective
We applied systems biology approaches to investigate circadian rhythmicity in rheumatoid arthritis (RA).
Methods
We recruited adults (age 16–80 years old) with a clinical diagnosis of RA (active disease [DAS28 > 3.2]). Sleep profiles were determined before inpatient measurements of saliva, serum, and peripheral blood mononuclear leukocytes (PBML). Transcriptome and proteome analyses were carried out by RNA-SEQ and LC-MS/MS. Serum samples were analysed by targeted lipidomics, along with serum from mouse collagen induced-arthritis (CIA). Bioinformatic analysis identified RA-specific gene networks and rhythmic processes differing between healthy and RA.
Results
RA caused greater time-of-day variation in PBML gene expression, and ex vivo stimulation identified a time-of-day-specific RA transcriptome. We found increased phospho-STAT3 in RA patients, and some targets, including phospho-ATF2, acquired time-of-day variation in RA. Serum ceramides also gained circadian rhythmicity in RA, which was also seen in mouse experimental arthritis, resulting from gain in circadian rhythmicity of hepatic ceramide synthases.
Conclusion
RA drives a gain in circadian rhythmicity, both in immune cells, and systemically. The coupling of distant timing information to ceramide synthesis and joint inflammation points to a systemic re-wiring of the circadian repertoire. Circadian reprogramming in response to chronic inflammation has implications for inflammatory co-morbidities and time-of-day therapeutics.
Original language | English |
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Article number | 47 |
Journal | Arthritis Research & Therapy |
Volume | 21 |
Issue number | 1 |
Early online date | 6 Feb 2019 |
DOIs | |
Publication status | Published - 2019 |
Keywords
- Arthritis
- Ceramide
- Circadian
- Immune cell
- Rheumatoid arthritis
Research Beacons, Institutes and Platforms
- Lydia Becker Institute
- Manchester Institute for Collaborative Research on Ageing