Abstract 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&amp;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. Graphical Abstract

Activity-dependent FosB gene expression negatively regulates mast cell functions