Association of Differential Mast Cell Activation to Granulocytic Inflammation in Severe Asthma.

BACKGROUND Mast cells (MC) play a role in inflammation and both innate and adaptive immunity but their involvement in severe asthma (SA) remains undefined. OBJECTIVE We investigated the phenotypic characteristics of the U-BIOPRED asthma cohort by applying published MC activation signatures to the sputum cell transcriptome. METHODS 84 SA, 20 mild/moderate (MMA) asthma, and 16 non-asthmatic healthy participants were studied. We calculated enrichment scores (ES) for nine MC activation signatures by asthma severity, sputum granulocyte status and three previously-defined sputum molecular phenotypes or transcriptome-associated clusters (TAC1, 2, 3) using gene-set variation analysis. RESULTS MC signatures except unstimulated, repeated FceR1-stimulated and IFNγ-stimulated were enriched in SA. A FceR1-IgE-stimulated and a single cell signature from asthmatic bronchial biopsies were highly enriched in eosinophilic asthma and in the TAC1 molecular phenotype. Subjects with a high ES for these signatures had elevated sputum levels of similar genes and pathways. IL-33- and LPS-stimulated MC signatures had greater ES in neutrophilic and mixed granulocytic asthma and in the TAC2 molecular phenotype. These subjects exhibited neutrophil, NF-κB, and IL-1β/TNFα pathway activation. The IFNγ-stimulated signature had the greatest ES in TAC2 and TAC3 that was associated with responses to viral infection. Similar results were obtained in an independent ADEPT asthma cohort. CONCLUSIONS Gene signatures of MC activation allow the detection of SA phenotypes and indicate that MC can be induced to take on distinct transcriptional phenotypes associated with specific clinical phenotypes. IL-33-stimulated MCs signature was associated with severe neutrophilic asthma while IgE-activated MC with an eosinophilic phenotype.