Lisa Koorneef¹, Elisabeth Gilis², Dorien Clarisse³, Leander Meuris⁴, Sara Dufour⁵, Daria Fijalkowska³, Julie Coudeneys², Annick Verhée³, Jonathan Thommis³, Matthias Kerkhofs³, Dirk Elewaut², Karolien De Bosscher³

(1) VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University; Department of Anatomy and Embryology, Leiden University Medical Center, Ghent / Leiden, Belgium / Netherlands. (2) VIB Center for Inflammation Research, Ghent University and Department of Rheumatology, Ghent University Hospital, Ghent, Belgium. (3) VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (4) VIB Center for Medical Biotechnology, Department of Biochemistry and Microbiology, Ghent, Belgium. (5) VIB Proteomics Core, Ghent , Belgium. 

Glucocorticoids (GCs) bind to the glucocorticoid receptor (GR) and are effective anti-inflammatories, a.o. against rheumatoid arthritis (RA), but also cause many (metabolic) side effects. Interestingly, peroxisome-proliferator activated nuclear receptor (PPAR) agonists counteract symptoms similar to GC side effects and suppress inflammation. This study explores how PPAR agonists influence the immunosuppressive and metabolic effects of GCs. DEX reduced the inflammatory TNFα response in mouse L929sA fibroblasts with a stably integrated E-selectin or IL-8-based luciferase reporter. This was further enhanced by PPARαagonist GW7647 and PPARγ agonist rosiglitazone, but not by other PPARα or PPARβ/δagonists. In collagen-induced arthritis mice, dexamethasone increased white adipose tissue weight and plasma triglyceride levels, which was (partially) counteracted by GW7647. However, GW7647 did not add to the DEX-mediated suppression of arthritis severity and immune cell counts. As a model mimicking RA more closely, fibroblast-like synoviocytes(FLS) were isolated from four female osteoarthritis patients and were stimulated with combinations of TNF, DEX and GW7647. FLS from all patients expressed GR, PPARα and PPARγ proteins. Expression of metabolic genes was increased by DEX and GW7647 alone and to a higher extent by their combination. Shot-gun proteomics revealed that the cooperative immunosuppression by DEX and GW7647 occurred in a pathway-specific manner. In conclusion, PPAR agonists can influence the metabolic effects of GCs, while the immunosuppressive effects depend more on context such as cell type and inflammatory pathway.