Glucocorticoids regulate lipid mediator networks by reciprocal modulation of 15-lipoxygenase isoforms affecting inflammation resolution.
Zhigang RaoElena BrunnerBenjamin GiszasAishwarya Iyer-BierhoffJana GerstmeierFriedemann BörnerPaul M JordanSimona PaceKatharina Paula Lydia MeyerRobert Klaus HofstetterDaniel MerkChristian PaulenzThorsten HeinzelPhilip C GrunertAndreas StallmachCharles Nicholas SerhanMarkus WernerOliver WerzPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
Glucocorticoids (GC) are potent anti-inflammatory agents, broadly used to treat acute and chronic inflammatory diseases, e.g., critically ill COVID-19 patients or patients with chronic inflammatory bowel diseases. GC not only limit inflammation but also promote its resolution although the underlying mechanisms are obscure. Here, we reveal reciprocal regulation of 15-lipoxygenase (LOX) isoform expression in human monocyte/macrophage lineages by GC with respective consequences for the biosynthesis of specialized proresolving mediators (SPM) and their 15-LOX-derived monohydroxylated precursors (mono-15-OH). Dexamethasone robustly up-regulated pre-mRNA, mRNA, and protein levels of ALOX15B/15-LOX-2 in blood monocyte-derived macrophage (MDM) phenotypes, causing elevated SPM and mono-15-OH production in inflammatory cell types. In sharp contrast, dexamethasone blocked ALOX15/15-LOX-1 expression and impaired SPM formation in proresolving M2-MDM. These dexamethasone actions were mimicked by prednisolone and hydrocortisone but not by progesterone, and they were counteracted by the GC receptor (GR) antagonist RU486. Chromatin immunoprecipitation (ChIP) assays revealed robust GR recruitment to a putative enhancer region within intron 3 of the ALOX15B gene but not to the transcription start site. Knockdown of 15-LOX-2 in M1-MDM abolished GC-induced SPM formation and mono-15-OH production. Finally, ALOX15B/15-LOX-2 upregulation was evident in human monocytes from patients with GC-treated COVID-19 or patients with IBD. Our findings may explain the proresolving GC actions and offer opportunities for optimizing GC pharmacotherapy and proresolving mediator production.
Keyphrases
- gas chromatography
- endothelial cells
- binding protein
- oxidative stress
- poor prognosis
- transcription factor
- dendritic cells
- anti inflammatory
- single cell
- sars cov
- low dose
- high dose
- genome wide
- adipose tissue
- high throughput
- magnetic resonance
- high glucose
- drug induced
- cell proliferation
- gene expression
- computed tomography
- palliative care
- magnetic resonance imaging
- mesenchymal stem cells
- signaling pathway
- long non coding rna
- smoking cessation
- intensive care unit
- respiratory failure
- newly diagnosed
- circulating tumor cells
- high resolution
- ulcerative colitis
- estrogen receptor