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.

中文翻译：

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糖皮质激素在受伤时抑制巨噬细胞向促炎表型的分化而不影响它们的迁移。

糖皮质激素药物广泛用于治疗免疫相关疾病，但其使用受到副作用和耐药性的限制，尤其是在以巨噬细胞为主的疾病中。为了改善糖皮质激素的治疗​​，需要对糖皮质激素作用机理进行更多的研究。在本研究中，我们已使用斑马鱼模型进行炎症反应，以研究糖皮质激素对先天免疫反应的影响。在斑马鱼的幼虫中，糖皮质激素治疗可抑制嗜中性粒细胞向损伤部位的迁移，而巨噬细胞的迁移则对糖皮质激素具有抵抗力。我们显示，合成糖皮质激素倍氯米松可减轻伤口诱导的编码中性粒细胞特异性趋化因子（Il8和Cxcl18b）的基因表达，但是，倍氯米松不会减弱巨噬细胞募集所需的编码Ccl2和Cxcl11aa的基因的诱导。在FACS分选的巨噬细胞上进行RNA测序表明，这些细胞中绝大多数由伤口引起的转录变化均受到倍氯米松抑制，而只有一小部分对糖皮质激素不敏感。结果，倍氯米松减少了分化为促炎性（M1）表型的巨噬细胞数量，我们使用tnfa：eGFP-F报告基因系和巨噬细胞形态分析。我们得出的结论是，巨噬细胞的分化和迁移受到独立调节，并且糖皮质激素使巨噬细胞的趋化迁移不受影响，但通过抑制它们向M1表型的分化而对这些细胞发挥抗炎作用。因此，巨噬细胞为主的疾病对糖皮质激素治疗的抗性不能归因于巨噬细胞对糖皮质激素的内在不敏感性。