(MRC DTP) Rhythmic regulation of chronic inflammation by endogenous glucocorticoids

Rheumatoid arthritis (RA) is a debilitating condition affecting 1% of the UK population. Patients suffering from RA often report diurnal (day-night) variation in disease symptoms, and clinical studies show elevations in circulating pro-inflammatory cytokines during the morning (Gibbs and Ray, 2013). It has been suggest that endogenous rhythms in adrenal secretion of the hormone cortisol (a glucocorticoid with anti-inflammatory functions) may underlie this rhythmic inflammation; with low circulating cortisol levels at night permitting increased inflammation during the early morning (Spies et al. 2014).

In our lab, using a mouse model of inflammatory arthritis, we have recently identified fibroblast-like synoviocytes (FLS) as a source of the rhythmic inflammatory signal within inflamed joints (Hand et al. 2016). We are now interested in examining how these pro-inflammatory cells respond both to endogenous glucocorticoid signals (i.e. cortisol/corticosterone) and therapeutic glucocorticoids used in the treatment of RA (i.e. prednisolone). To this effect, we have developed a transgenic mouse in which we have conditionally knocked out the glucocorticoid receptor (GR) in FLS.

Using a combination of in vitro and in vivo approaches we will investigate how the chronic inflammatory state induced by arthritis affects rhythms of endogenous glucocorticoids, expression of their receptor, and their function. Further work will characterize the circadian and inflammatory function of inflammatory cells lacking GR and assess how loss of the GR in key cell types impacts on disease incidence and severity, disease rhythmicity, and response to therapeutics.