Transcriptional Heterogeneity of Mast Cells and Basophils upon Activation

Mast cells and basophils are developmentally related cells whose activation is a hallmark of allergy. Functionally, mast cells and basophils overlap in their ability to produce several mediators, including histamine and granule proteases, but studies have increasingly demonstrated nonredundant roles. To characterize the transcriptional heterogeneity of mast cells and basophils upon their activation, we performed large-scale comparative microarrays of murine bone marrow-derived mast cells and bone marrow-derived basophils (BMBs) at rest, upon an adaptive-type activation (IgE cross-linking), or upon an innate-type activation (IL-33 stimulation). Hierarchical clustering demonstrated that bone marrow-derived mast cells and BMBs shared specific activation-associated transcriptional signatures but differed in other signatures both between cell type and between activation mode. In bone marrow-derived mast cells, IgE cross-linking upregulated 785 genes, including Egr2, Ccl1, and Fxyd6, whereas IL-33 stimulation induced 823 genes, including Ccl1, Egr2, and Il1b. Focused bioinformatics pathway analysis demonstrated that IgE activation aligned with processes such as oxidative phosphorylation, angiogenesis, and the p53 pathway. The IL-33-activated transcriptome was enriched in genes commonly altered by NF-κB in response to TNF, by IL-6 via STAT3, and in response to IFN-γ. Furthermore, BMBs activated via IgE cross-linking selectively induced immune response genes Ccl1, Il3, and Il2 compared with IL-33-stimulated BMBs. Principal-component analysis revealed key cell- and activation-specific clustering. Overall, our data demonstrate that mast cells and basophils have cell- and activation-specific transcriptional responses and suggest that context-specific gene networks and pathways may shape how the immune system responds to allergens and innate cytokines.