Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration
Glucocorticoid 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 a...
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doaj-ae44fcdf94fb41dba77966bbc925c38b2020-11-25T01:55:04ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-05-0112510.1242/dmm.037887037887Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migrationYufei Xie0Sofie Tolmeijer1Jelle M. Oskam2Tijs Tonkens3Annemarie H. Meijer4Marcel J. M. Schaaf5 Animal Science and Health Cluster, Institute of Biology, Leiden University, 2333CC Leiden, The Netherlands Animal Science and Health Cluster, Institute of Biology, Leiden University, 2333CC Leiden, The Netherlands Animal Science and Health Cluster, Institute of Biology, Leiden University, 2333CC Leiden, The Netherlands Animal Science and Health Cluster, Institute of Biology, Leiden University, 2333CC Leiden, The Netherlands Animal Science and Health Cluster, Institute of Biology, Leiden University, 2333CC Leiden, The Netherlands Animal Science and Health Cluster, Institute of Biology, Leiden University, 2333CC Leiden, The Netherlands Glucocorticoid 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, whereas migration of macrophages is glucocorticoid resistant. We show that wounding-induced increases in the expression of genes that encode 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 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.http://dmm.biologists.org/content/12/5/dmm037887GlucocorticoidsInflammationMacrophage differentiationLeukocyte migrationZebrafishTail amputation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yufei Xie Sofie Tolmeijer Jelle M. Oskam Tijs Tonkens Annemarie H. Meijer Marcel J. M. Schaaf |
spellingShingle |
Yufei Xie Sofie Tolmeijer Jelle M. Oskam Tijs Tonkens Annemarie H. Meijer Marcel J. M. Schaaf Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration Disease Models & Mechanisms Glucocorticoids Inflammation Macrophage differentiation Leukocyte migration Zebrafish Tail amputation |
author_facet |
Yufei Xie Sofie Tolmeijer Jelle M. Oskam Tijs Tonkens Annemarie H. Meijer Marcel J. M. Schaaf |
author_sort |
Yufei Xie |
title |
Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration |
title_short |
Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration |
title_full |
Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration |
title_fullStr |
Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration |
title_full_unstemmed |
Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration |
title_sort |
glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2019-05-01 |
description |
Glucocorticoid 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, whereas migration of macrophages is glucocorticoid resistant. We show that wounding-induced increases in the expression of genes that encode 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 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. |
topic |
Glucocorticoids Inflammation Macrophage differentiation Leukocyte migration Zebrafish Tail amputation |
url |
http://dmm.biologists.org/content/12/5/dmm037887 |
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