The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages

Clayton, Sally A; Lockwood, Chloe; O’Neil, John D; Daley, Kalbinder K; Hain, Sofia; Abdelmottaleb, Dina; Bolimowska, Oliwia O; Tennant, Daniel A; Clark, Andrew R

doi:10.1093/discim/kyad027

Cited by 3 publications

(1 citation statement)

References 56 publications

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“…Environmental conditions were 21 ± 2 • C and 55 ± 10% relative humidity and a 12 h lightdark cycle. Hind limb tibiae from mice were dissected, and the bone marrow was collected though centrifugation at 10,000× g for 15 s in media containing RPMI, 1% FBS, and 1% Penicillin Streptomycin Solution (all from Sigma-Aldrich), as previously described [27]. Cells were cultured (1 × 10 6 ) for up to 8 days in culture media (RPMI, supplemented with 10% foetal bovine serum (Biosera), 2 mM L-glutamine, 100 mg/mL streptomycin, 100 U/mL penicillin (all from Sigma-Aldrich)) for 72 h prior to treatment with M-CSF (50 ng/mL, Abcam, Cambridge, UK) and S1P (1 µM).…”

Section: Murine Bmdm Isolation and Culturementioning

confidence: 99%

The Species Effect: Differential Sphingosine-1-Phosphate Responses in the Bone in Human Versus Mouse

Frost,

Lewis,

Jones

et al. 2024

IJMS

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The deterioration of osteoblast-led bone formation and the upregulation of osteoclast-regulated bone resorption are the primary causes of bone diseases, including osteoporosis. Numerous circulating factors play a role in bone homeostasis by regulating osteoblast and osteoclast activity, including the sphingolipid—sphingosine-1-phosphate (S1P). However, to date no comprehensive studies have investigated the impact of S1P activity on human and murine osteoblasts and osteoclasts. We observed species-specific responses to S1P in both osteoblasts and osteoclasts, where S1P stimulated human osteoblast mineralisation and reduced human pre-osteoclast differentiation and mineral resorption, thereby favouring bone formation. The opposite was true for murine osteoblasts and osteoclasts, resulting in more mineral resorption and less mineral deposition. Species-specific differences in osteoblast responses to S1P were potentially explained by differential expression of S1P receptor 1. By contrast, human and murine osteoclasts expressed comparable levels of S1P receptors but showed differential expression patterns of the two sphingosine kinase enzymes responsible for S1P production. Ultimately, we reveal that murine models may not accurately represent how human bone cells will respond to S1P, and thus are not a suitable model for exploring S1P physiology or potential therapeutic agents.

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Section: Murine Bmdm Isolation and Culturementioning

confidence: 99%

The Species Effect: Differential Sphingosine-1-Phosphate Responses in the Bone in Human Versus Mouse

Frost,

Lewis,

Jones

et al. 2024

IJMS

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Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells

DeCuzzi,

Oberbauer,

Chmiel

et al. 2024

Preprint

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RATIONALE: Spatially coordinated ERK signaling events (SPREADs) transmit radially from a central point to adjacent cells via secreted ligands for EGFR and other receptors. SPREADs maintain homeostasis in non-pulmonary epithelia, but it is unknown whether they play a role in the airway epithelium or are dysregulated in inflammatory disease. OBJECTIVES: (1) To characterize the spatial heterogeneity of ERK activity in response to pro-inflammatory ligands, and (2) to assess the effects of pharmacological and metabolic regulators on cytokine-mediated SPREADs. METHODS: Live-cell ERK biosensor activity and SPREAD events were measured in human bronchial epithelial cell lines (HBE1 and 16HBE) and primary human bronchial epithelial cells (pHBE), in both submerged and biphasic Air-Liquid Interface (ALI) culture conditions (i.e., differentiated cells). Cells were exposed to pro-inflammatory cytokines relevant to asthma and chronic obstructive pulmonary disease (COPD), and to pharmacological treatments (gefitinib, tocilizumab, hydrocortisone) and metabolic modulators (insulin, 2-deoxyglucose) to probe the airway epithelial mechanisms of SPREADs. Phospho-STAT3 immunofluorescence was used to measure localized inflammatory responses to IL-6. MEASUREMENTS AND MAIN RESULTS: Pro-inflammatory cytokines significantly increased the frequency of SPREADs. Notably, differentiated pHBE cells display increased SPREAD frequency that coincides with airway epithelial barrier breakdown. SPREADs correlate with IL-6 peptide secretion and localized pSTAT3. Hydrocortisone, inhibitors of receptor signaling, and suppression of metabolic function decreased SPREADs and local STAT3 activation. CONCLUSIONS: Pro-inflammatory cytokines modulate SPREADs in human airway epithelial cells via both secreted EGFR and IL6R ligands. SPREADs correlate with changes in epithelial barrier permeability, implying a role for spatiotemporal ERK signaling in barrier homeostasis and dysfunction during inflammation. The involvement of SPREADs in airway inflammation suggests a novel signaling mechanism that could be exploited clinically to supplement corticosteroid treatment for asthma and COPD.

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Journey through discovery of 75 years glucocorticoids: evolution of our knowledge of glucocorticoid receptor mechanisms in rheumatic diseases

Eiers,

Vettorazzi,

Tuckermann

2024

Ann Rheum Dis

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For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis.

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The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages

Cited by 3 publications

References 56 publications

The Species Effect: Differential Sphingosine-1-Phosphate Responses in the Bone in Human Versus Mouse

The Species Effect: Differential Sphingosine-1-Phosphate Responses in the Bone in Human Versus Mouse

Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells

Journey through discovery of 75 years glucocorticoids: evolution of our knowledge of glucocorticoid receptor mechanisms in rheumatic diseases

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