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Glucocorticoid transcriptome in macrophages upon activation [RNA-seq]

ABSTRACT: Glucocorticoids (GCs) are lifesaving medicines prescribed to treat inflammatory diseases. GCs act on numerous cell types and tissue of the body, however, one of the most important effects are their ability to suppress the immune system. Synthetic glucocorticoids, exemplified by dexamethasone (Dex) and prednisone, rank among the most widely prescribed anti-inflammatory and immunomodulatory drugs globally. The therapeutic efficacy of glucocorticoids extents across a broad spectrum of immune diseases, including conditions like acute and chronic inflammation. The action of the glucocorticoids in immune cells is mediated by the glucocorticoid receptor (here after GR; encoded by Nr3c1 gene) that is a member of the nuclear receptor superfamily of ligand dependent transcription factors. Macrophages emerge as central targets for the anti-inflammatory actions of glucocorticoids during periods of inflammation. Macrophages play a pivotal role during hyperinflammation and cytokine storm, two processes intricately linked to NLRP3 inflammasome activation in human diseases. Upon activation macrophages undergo a process of transcriptional reprogramming to resolve inflammation and restore homeostasis. To elucidate how glucocorticoids impact the transcriptome of macrophages upon activation, RNA-seq was performed on RNA isolated from macrophages unpolarized (M0) and polarized to M1 and M2 profile from WT and GRKO treated with vehicle and Dex. In addition, M0 and LPS M1-like macrophages were treated with vehicle and Dex and then analyzed by Cut&Tag.

ORGANISM(S): Mus musculus

PROVIDER: GSE306502 | GEO | 2026/02/11

REPOSITORIES: GEO

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Project description:Introduction: Glucocorticoids (GC) are one of the most common anti-inflammatory treatments for autoimmune diseases such as systemic lupus erythematosus (lupus). Chronic use of GCs leads to several deleterious side-effects and diminished quality of life, inciting a need for steroid-sparing therapeutics. Polyunsaturated fatty acids (PUFA), such as docosahexaenoic acid (DHA), have been shown to inhibit proinflammatory and Type I Interferon (IFN) gene signatures in macrophages, which are central to initiation of autoimmunity triggered by inhaled environmental toxicants such as bacterial lipopolysaccharide (LPS). The goal of the present study was to determine whether combination treatment with suboptimal concentrations of DHA and GC in LPS-primed alveolar-like macrophages could potentiate the anti-inflammatory effects of DHA and GC individual treatment. Methods: RNAseq was used to evaluate whether DHA could potentiate the anti-inflammatory effects of the GC dexamethasone (DEX) in LPS-stimulated fetal liver-derived alveolar-like macrophages (FLAMs) isolated from NZBWF1 lupus-prone mice. FLAMs were treated were treated with suboptimal concentrations of either DHA alone, DEX alone, or DHA+DEX in combination prior to LPS stimulation (20 ng/mL) for 4 or 8 hr. Results: LPS stimulation resulted in significant enrichment of innate immunity and Type I/II IFN pathways with corresponding upregulation of gene sets falling under these pathways at both timepoints. LPS-primed FLAMs treated in combination with suboptimal concentrations of DHA and DEX exhibited combinatorial affects greater than DHA and DEX treatment alone. DHA+DEX co-treatment resulted in downregulation of innate immunity and Type I/II IFN pathways initially altered by LPS treatment. Lastly, DHA+DEX co-treatment exhibited superior downregulation of individual Type I/II IFN genes compared to DHA and DEX treatment alone. Discussion: Our findings demonstrate that while DHA and DEX can significantly alter LPS-stimulated gene expression in alveolar-like macrophages when used in high enough concentrations alone, DHA can be used to potentiate the anti-inflammatory effects of DEX when both are used at lower concentrations. This study provides promising evidence that DHA can potentially be used to lower requisite amounts GCs required to reduce inflammation.

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Glucocorticoid transcriptome in macrophages upon activation [RNA-seq]

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