The synthetic derivatives of our ‘stress’ hormones, glucocorticoids, are successfully used in the clinic as anti-inflammatory and immunosuppressive agents. This suggests that the production of our own (endogenous) glucocorticoids may not be sufficient under pathological conditions. Our group focuses on dissecting the effects of endogenous glucocorticoids on different cells of the immune system, both under basal and pathological conditions. Glucocorticoids primarily act via the glucocorticoid receptor (GR), also known as NR3C1, a member of the nuclear receptor family that shows ubiquitous expression. We and others have shown that critical effects of glucocorticoids are mediated in a cell-type and experimental disease model-dependent manner (see Figure). Recently, we reported that the GR is critical for Foxp3+ regulatory T-cell (Treg cell) function in experimental inflammatory colitis, suggesting that endogenous glucocorticoids strengthen Treg cell function in the intestine (Lourdes Rocamore-Reverte et al. Front. Immunol. 2019;10:472).
We have also generated a mouse model with a selective loss of the GR in B-cells in order to study the role of glucocorticoids in B-cell development and function (antibody synthesis, immune response regulation). Our aim is to find target cells that are critical for glucocorticoid therapy in a disease model-dependent manner. This requires the need to develop a therapeutic strategy to deliver glucocorticoids in a cell-specific manner. A huge advantage of such an approach is the reduction of the strong side-effects these hormones have on other tissues such as bones (osteoporosis) and muscles (atrophy).
If you are interested in these topics, please contact the PI Jan Wiegers.
Figure: Immune cell-specific targeting of the GR.
Global loss of the GR is lethal. Red crosses show the cell types where the GR has been specifically deleted so far. Macrophages + Dendritic cells: Lethal after infection with parasites or injection with superantigen. T-cells (total): Lethal upon treatment with polyclonal T-cell activating agents. Foxp3+ Treg cells: Defective suppression of experimental inflammatory colitis. B-cells: Not known.
Adapted from G. Dranoff 2004 Nature Reviews Cancer 4: 11