Mast cell-specific inactivation of Fosb exacerbates release of pro-inflammatory mediators in models of systemic anaphylaxis and lipopolysaccharide-induced sepsis

Abstract Mast cells (MC) are innate immune cells that can orchestrate diverse physiologic and pathologic responses. This is due to the MC capacity to respond to a variety of stimuli and selectively release a diverse repertoire of mediators including prestored granule mediators, cytokines, growth factors and neurotransmitters. This vast heterogeneity in MC functions implies that their transcriptional profile needs to be extensively regulated, but the underlying mechanisms are not understood. Our previous data showed that MC expression of FosB and ΔFosB, two transcription factors formed by alternative splicing of the FosB gene, is markedly upregulated in response to a variety of stimuli, including IgE-antigen activation and stress, but the role of MC-specific FosB and ΔFosB in MC function remains unexplored. Here we crossed Mcpt5-Cre mice with a Cre-dependent floxed FosB mouse strain (Mcpt5-Cre;FosB (fl/fl)) to assess the role of MC-specific FosB expression. Bone marrow derived mast cells from Mcpt5-Cre;FosB (fl/fl) mice exhibited increased IgE-antigen mediated histamine release. Using a passive systemic anaphylaxis model, we next found that Mcpt5-Cre;FosB (fl/fl) mice exhibited greater serum histamine levels, and more severe hypothermia and clinical scores, compared with Mcpt5-Cre-negative controls. Mcpt5-Cre;FosB (fl/fl) mice also showed exacerbated hypothermia and serum IL-6 levels in response to lipopolysaccharide (LPS) (1 mg/Kg) injection. Together, these data demonstrate that MC Fosb expression exerts a negative regulation on MC mediator release and associated inflammatory responses. Ongoing studies using CUT&RUN-sequencing aim to identify the down_stream targets of FosB and ΔFosB in MCs.