A Review: Mast Cells as Targets for Glucocorticoid Action.

PURPOSE OF REVIEW: This review aims to summarize the established and potential targets of glucocorticoids (GCs) on mast cells, which are implicated in the pathophysiology of various allergic and inflammatory diseases including asthma, allergic rhinitis, and atopic dermatitis. We sought to answer the following questions: (1) How do glucocorticoids inhibit the release of mediators from mast cells? (2) What are the effects of glucocorticoids on mast cell signaling molecules? (3) By what mechanisms do glucocorticoids induce mast cell apoptosis? and (4) What are the genomic and non-genomic mechanisms underlying these effects?

RECENT FINDINGS: Evidence published since 2020 reinforces that glucocorticoid effects on mast cells are context dependent rather than uniform. Dexamethasone can directly suppress selected functions of human and murine mast cells, including in combination with inhibitory CD300a signaling [22]. Conversely, activated human lung mast cells can reduce corticosteroid responsiveness in neighboring airway smooth muscle cells by altering glucocorticoid-regulated transcription [23]. In patients with asthma, six weeks of inhaled budesonide reduced airway mast cell infiltration and improved airway hyperresponsiveness; importantly, associations differed according to mast cell phenotype, airway location, and inflammatory phenotype [25]. Single-cell studies now reveal multiple human mast cell transcriptional states across tissues [7, 8], while integrated RNA-seq and H3K27ac profiling in primary human mast cells demonstrates selective regulation of mast-cell identity genes and super-enhancer networks [92]. These findings place glucocorticoid responsiveness within a framework of mast cell state, tissue niche, species, glucocorticoid compound, and experimental context. Glucocorticoid-associated mast cell depletion may involve reduced stromal/fibroblast-derived SCF and, in IL-3-dependent murine models, reduced IL-3 receptor expression; these are mechanistically distinct effects. Glucocorticoids can target mast cells at several levels, including mediator synthesis and release, intracellular signaling, survival, and transcriptional regulation, but the magnitude and nature of these effects vary substantially among species, tissue compartments, mast cell phenotypes/states, glucocorticoid compounds, activation pathways, and experimental conditions. Classical GR-dependent transcription involves GRE-dependent regulation and interactions with transcription factors such as NF-κB and AP-1, yet mast-cell-specific GR-regulated gene and chromatin programs remain incompletely defined. Rapid effects on degranulation are also unresolved, with evidence for membrane-associated classical GR signaling as well as other rapid mechanisms. Contemporary human and single-cell data therefore argue against treating mast cells as a single uniformly corticosteroid-responsive population. Future studies should define the molecular basis of rapid glucocorticoid signaling and map GR-responsive transcriptional and chromatin programs across primary human mast cell states and tissue niches.