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Adenosine-specific transcriptional programs in murine connective tissue type mast cells

ABSTRACT: Mast cells are tissue-resident immune cells that are critical for the pathogenesis of allergic and inflammatory disorders. Their physiological functions include host defense against parasites and, more recently, food quality control through antigen avoidance. The purine nucleoside adenosine (ADO), like other mast cell activators, such as antigens or Mrgprb2 agonists, increases intracellular Ca2+ concentration; however, it fails to induce degranulation of preformed mediators when applied to mast cells alone, and there is limited knowledge of whether ADO evokes the de novo synthesis and release of inflammatory mediators in tissue mast cells. An unbiased genome-wide analysis of gene expression triggered by various mast cell activators should enable identification of the gene program specifically activated by ADO in mast cells and thereby reveal new components of the associated inflammatory responses. Here, we performed bulk RNA sequencing in primary murine peritoneal mast cells (PMCs) as connective tissue mast cells. By comparing responses evoked by ADO stimulation with those of the Mrgprb2 agonist compound 48/80 and antigens activating FcεRI receptors, we identified 393 genes uniquely regulated by ADO, including genes encoding the de novo synthesized mediators transforming growth factor α and interleukin 7. Transcription factor activity inference, protein classification, functional enrichment analysis, protein interaction network, and topology analysis revealed a distinct ADO-specific transcriptional gene program involved in phosphoinositide signaling, vesicle trafficking, glycolysis, mitochondrial activity, and cell cycle arrest. The functional relevance of the identified de novo synthesized mediators for ADO-evoked inflammatory reactions can be evaluated in future studies.

ORGANISM(S): Mus musculus

PROVIDER: GSE324337 | GEO | 2026/03/10

REPOSITORIES: GEO

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Project description:Mast cells are innate immune cells that play a crucial role in numerous physiological processes across tissues by releasing pre-stored and newly synthesized mediators in response to stimuli, an activity largely driven by changes in gene expression. Given their widespread influence, dysfunction in mast cells can contribute to a variety of pathologies including allergies, long COVID, and autoimmune and neuroinflammatory disorders. Despite this, the specific transcriptional mechanisms that control mast cell mediator release remain poorly understood, significantly hindering the development of effective therapeutic strategies. We found that the two proteins encoded by the transcription factor FosB, FOSB and the highly stable variant ΔFOSB, are robustly expressed upon stimulation in both murine and human mast cell progenitors. Motivated by these findings, we generated a novel mouse model with targeted ablation of FosB gene expression specifically in mast cells (MC FosB- ) by crossing a mast cell-specific Cre reporter line (Mcpt5-Cre) with a Cre-dependent floxed FosB mouse lines. We found that mast cell progenitors derived from MC FosB- mice, compared to wild types (WT), exhibit baseline increased histamine content and vesicle numbers. Additionally, they show enhanced calcium mobilization, degranulation, and histamine release following allergy-related IgE-mediated stimulation, along with heightened IL-6 release in response to infection-like LPS stimulation. In vivo experiments with IgE- mediated and LPS challenges revealed that MC FosB- mice experience greater drops in body temperature, heightened activation of tissue-resident mast cells, and increased release of pro-inflammatory mediators compared to their WT counterparts. These findings suggest that FosB products play a crucial regulatory role in moderating stimulus-induced mast cell activation in response to both IgE and LPS stimuli. Lastly, by integrating CUT&RUN and RNAseq data, we identified several genes targeted by ΔFOSB that could mediate these observed effects, including Mir155hg, CLCF1, DUSP4, and Trib1. Together, this study provides the first evidence that FOSB/ΔFOSB modulate mast cell functions and provides a new possible target for therapeutic interventions aimed at ameliorating mast cell-related diseases.

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Adenosine-specific transcriptional programs in murine connective tissue type mast cells

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