|ZFIN ID: ZDB-PUB-190511-2|
Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration
Xie, Y., Tolmeijer, S., Oskam, J.M., Tonkens, T., Meijer, A.H., Schaaf, M.J.M.
|Source:||Disease models & mechanisms 12(5): (Journal)|
|Registered Authors:||Meijer, Annemarie H., Schaaf, Marcel J. M., Xie, Yufei|
|Keywords:||Glucocorticoids, Inflammation, Leukocyte migration, Macrophage differentiation, Tail amputation, Zebrafish|
|PubMed:||31072958 Full text @ Dis. Model. Mech.|
Xie, Y., Tolmeijer, S., Oskam, J.M., Tonkens, T., Meijer, A.H., Schaaf, M.J.M. (2019) Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration. Disease models & mechanisms. 12(5):.
ABSTRACTGlucocorticoid drugs are widely used to treat immune-related diseases, but their use is limited by side effects and by resistance, which especially occurs in macrophage-dominated diseases. In order to improve glucocorticoid therapies, more research is required into the mechanisms of glucocorticoid action. In the present study, we have used a zebrafish model for inflammation to study glucocorticoid effects on the innate immune response. In zebrafish larvae, the migration of neutrophils towards a site of injury is inhibited upon glucocorticoid treatment, while migration of macrophages is glucocorticoid resistant. We show that wounding-induced increases in expression of genes encoding neutrophil-specific chemoattractants (Il8 and Cxcl18b) are attenuated by the synthetic glucocorticoid beclomethasone, but that beclomethasone does not attenuate the induction of the genes encoding Ccl2 and Cxcl11aa, which are required for macrophage recruitment. RNA sequencing on Fluorescence-Activated Cell Sorting (FACS)-sorted macrophages shows that the vast majority of the wounding-induced transcriptional changes in these cells are inhibited by beclomethasone, whereas only a small subset is glucocorticoid-insensitive. As a result, beclomethasone decreases the number of macrophages that differentiate towards a pro-inflammatory (M1) phenotype, which we demonstrated using a tnfa:eGFP-F reporter line and analysis of macrophage morphology. We conclude that differentiation and migration of macrophages are regulated independently, and that glucocorticoids leave the chemotactic migration of macrophages unaffected, but exert their anti-inflammatory effect on these cells by inhibiting their differentiation to an M1 phenotype. The resistance of macrophage-dominated diseases to glucocorticoid therapy can therefore not be attributed to an intrinsic insensitivity of macrophages to glucocorticoids.