Chronic inflammatory arthritis drives systemic changes in circadian energy metabolism

Polly Downton, Fabio Sanna, Robert Maidstone, Toryn Poolman, Edward Hayter, Suzanna Dickson, James Early, Antony Adamson, David Spiller, Devin Simpkins, Matthew Baxter, Roman Fischer, Magnus Rattray, Andrew Loudon, Julie Gibbs, David Bechtold, David Ray

Research output: Contribution to journalArticlepeer-review


Chronic inflammation underpins many human diseases. Morbidity and mortality associated with chronic inflammation are often mediated through metabolic dysfunction. Inflammatory and metabolic processes vary through circadian time, suggesting an important temporal crosstalk between these systems. Using an established mouse model of rheumatoid arthritis, we show that chronic inflammatory arthritis results in rhythmic joint inflammation and drives major changes in muscle and liver energy metabolism and rhythmic gene expression. Transcriptional and phosphoproteomic analyses revealed alterations in lipid metabolism and mitochondrial function associated with increased EGFR-JAK-STAT3 signaling. Metabolomic analyses confirmed rhythmic metabolic rewiring with impaired β-oxidation and lipid handling and revealed a pronounced shunt toward sphingolipid and ceramide accumulation. The arthritis-related production of ceramides was most pronounced during the day, which is the time of peak inflammation and increased reliance on fatty acid oxidation. Thus, our data demonstrate that localized joint inflammation drives a time-of-day–dependent build-up of bioactive lipid species driven by rhythmic inflammation and altered EGFR-STAT signaling.
Original languageEnglish
Article number2112781119
Publication statusPublished - 3 May 2022


  • ceramide; circadian clock; inflammation; mitochondria; rheumatoid arthritis.


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