Rheumatoid arthritis reprograms circadian output pathways

Abstract

ObjectiveWe applied systems biology approaches to investigate circadian rhythmicity in rheumatoid arthritis (RA).MethodsWe 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.ResultsRA 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.ConclusionRA 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.Electronic supplementary materialThe online version of this article (10.1186/s13075-019-1825-y) contains supplementary material, which is available to authorized users.

Circadian rhythms in innate immunity and stress responses

“…1), wherein the circadian clock is subject to inflammation-mediated reprogramming, with eventual disruption of the clock mechanism. 46 Immune and inflammatory responses come at a high energetic cost and therefore necessitate that immune and metabolic processes are coupled to ensure energetic demands are met. We propose that the circadian clock is such a coupling mechanism, and that during inflammation the circadian processes are extensively re-organized, with attenuation of many usual transcriptional rhythms and de novo genesis of surrogate cycling pathways.…”

MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice

“…Recent studies have shown that nutritional challenges including high fat and ketogenic diets can reprogram extensively and in a tissue-specific manner the mouse circadian physiology 15 , 17 – 19 . This reprogramming is also observed in case of diseases such as rheumatoid arthritis 16 . In the present work we used the MCDD experimental paradigm to study the link between circadian timing and the development of steatohepatitis in the mouse.…”

“…Consistently, epidemiological studies increasingly support the notion that a poorly synchronized or disrupted CTS is an important risk factor for the development of many chronic metabolic diseases including dyslipidemia, overweight and insulin resistance, and cancer 11 – 13 . Reciprocally, circadian physiology can be altered by diseases 14 – 16 . This is exemplified by the reprogramming of the liver and serum metabolome as well as hepatic transcriptome occurring in obese mice 17 – 20 .…”

KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism

“…Alteration of the rhythmic hepatic transcriptome in Klf10 Δhep mice also led to de novo oscillation for a large number of genes, reminiscent of the transcriptional changes occurring in KLF15 deficient cardiomyocytes (Zhang et al, 2015, p. 15). In addition to the genetic disruption of clock-controlled KLFs, a variety of other systemic perturbations including high fat and ketogenic diet challenges, arrhythmic feeding, calorie restriction, alcohol consumption, lung cancer and rheumatoid arthritis also generate de novo circadian oscillations in the liver (Eckel-Mahan et al, 2013;Gaucher et al, 2019;Greenwell et al, 2019;Makwana et al, 2019;Masri et al, 2016;Poolman et al, 2019;Tognini et al, 2017). Unchallenged Klf10 Δhep mice appear healthy but are prone to develop hepatic steatosis when fed with high sugar while Klf10 -/mice develop greater liver injury in a non-alcoholic steatohepatitis (NASH) model (Leclère et al, 2020).…”