Insights Into The Heterogeneity Of Constitutive and Inducible Mast Cells In Inflammation and Homeostasis

Background: Mast cell (MCs) activation and expansion is a common feature of human diseases driven by type 2 (T2) inflammation, including asthma, food allergy and eosinophilic esophagitis. While discrete MC phenotypes are recognized based on protease expression profiles, the full degree of MCs heterogeneity is poorly understood.

Methods: Here, we use transcriptomics to comprehensively characterize MC heterogeneity in steady state, including skin, heart, palate, tongue, adipose tissue, peritoneal cavity, bone marrow and spleen. To assess MCs phenotype during inflammation, MCs were isolated from Nippostrongylus brasiliensis infected lungs and subcutaneous adenocarcinoma tumors. Basophils were isolated from several tissues for comparison.

Results: We find substantial MC heterogeneity across tissues and disease states. In addition to canonical MC proteases, MCs differentially expressed a range of signaling and activating receptors, and pro-inflammatory mediators. A number of transcripts upregulated within murine adenocarcinomas were similarly observed in human adenocarcinomas, suggesting a shared tumor-associated program across species. Inflammation-expanded MCs were found to retain a BM-associated transcriptional ‘fingerprint’ that included the basophil-associated transcript Mcpt8, which expression was further confirmed using a Mcpt8 reporter strain.

Conclusions: These results underline the extraordinarily transcriptional heterogeneity of MCs exhibiting tissue specific responses, providing new insights into MCs in homeostasis and T2 inflammation.