In the EU, 15 million people annually take systemic glucocorticoids (GCs) such as dexamethasone. GCs bind to the glucocorticoid receptor (GR) and effectively suppress inflammation, but may cause side effects such as insulin resistance and dyslipidemia. Interestingly, peroxisome-proliferator activated nuclear receptor α (PPARα) agonists also suppress inflammation and counteract symptoms similar to GC side effects. Therefore, we will investigate whether selective PPARα agonism can enhance anti-inflammatory actions of dexamethasone while reducing (metabolic) side effects in a mouse model of collagen-induced rheumatoid arthritis (RA). Since human fibroblast-like synoviocytes (FLS) are the main targets of GC treatment in RA, we will also investigate how GR and PPARα agonism affects the transcriptome and secretome in TNF-stimulated human FLS. To decipher receptor crosstalk mechanisms, we will evaluate the composition of the transcriptional GR and PPARα complexes, as well as receptor binding patterns to the genome in murine fibroblasts. All in all, this study will provide a fundamental insight into how nuclear receptor crosstalk opens up opportunities for better therapeutic strategies in rheumatic diseases.