The glucocorticoid receptor (GR) orchestrates the crosstalk between fibroblast-like synoviocytes and macrophages to reduce Inflammation in arthritis

Introduction:

Glucocorticoids (GCs) are used to suppress inflammation to treat rheumatoid arthritis (RA), despite severe side effects. Enhanced understanding of the molecular mechanisms of GCs will help to improve treatment strategies. GCs bind to the Glucocorticoid Receptor (GR), a ligand-induced transcription factor acting either in a monomeric or a homo-dimeric form to modulate gene expression. Until recently, GR in immune cells was considered to be responsible for mediating the anti-inflammatory effects of GCs. We challenged this concept and showed that GR in fibroblast-like synoviocytes (FLS) is essential to mediate suppression of inflammation by GCS in serum transferred arthritis.

Results:

Mice lacking GR and with hampered GR dimerization capacity in all cell types but with intact GR in the hematopoietic compartment including circulating immune cells, showed no sufficient suppression of arthritis. Impaired GR function in immune cells, but with intact GR in stromal cells, such as FLS, suffices to reduce inflammation. Further investigations showed that the GR in FLS mediates the induction of anti-inflammatory macrophages, indicating a cross-talk between FLS and macrophages.

Discussion:

The aim of my thesis is now to decipher the molecular determinants regulated by the GR in FLS, which are necessary for the cross-talk to macrophages to induce an anti-inflammatory phenotype. To this end I plan to include transcriptomics and co-culture systems for functional validation and the analysis of compound mutant mice.

Key words:

Glucocorticoids, Glucocorticoid Receptor, Cross-Talk, Inflammation, Arthritis