TGF-β drives differentiation of intraepithelial mast cells in inflamed airway mucosa

Abstract

Similarly to acute intestinal helminth infection, several conditions of chronic eosinophilic type 2 inflammation of mucosal surfaces, including asthma and eosinophilic esophagitis, feature robust expansions of intraepithelial mast cells (MCs). Also the hyperplastic mucosa of nasal polyposis in the context of chronic rhinosinusitis, with or without COX1 inhibitor intolerance, contains impressive numbers of intraepithelial MCs. In this issue of the JCI, Derakhshan et al. elucidate the heterogeneity of MCs in nasal polyposis and identify a transcriptional signature of TGF-β target genes expressed by the intraepithelial MC population. These MCs displayed effector functions that implicate them as pathogenetic contributors. TGF-β directed differentiation of similar MC populations also in vitro. These findings extend the emerging concept of TGF-β as a driver of type 2 inflammation at barrier surfaces.

Figure 1. TGF-β directs differentiation of inflammatory intraepithelial MCs in NP.

Steady-state nasal mucosa contains few MC_T within the respiratory epithelium or in glandular epithelial structures. In CRS, chronic exposure to pathogenetic factors compromises epithelial homeostasis and triggers subepithelial eosinophilic type 2 inflammation. Inflammatory stimuli drive expansion of intraepithelial MC_Ts into a large population by proliferation of MMCs and recruitment of bone marrow–derived MC progenitors (MC_p). The findings of Derekhshan et al. (1) suggest that stress or damage results in enhanced expression of TGF-β by epithelial cells. TGF-β drives differentiation of an inflammatory MC_T phenotype (iMC_T) with expression of CPA3, IL-5, and increased production of cysteinyl leukotrienes (Cys-LT). MC_T-derived factors may be key for initiating and/or sustaining the pathogenic type 2 inflammation and hyperplasia of epithelial and stromal compartments.