Maturation of mast cell progenitors to mucosal mast cells during allergic pulmonary inflammation in mice

In contrast to resident constitutive mast cells (CMCs), mucosal MCs (MMCs) appear in lung and trachea of sensitized mice only following inhalation challenge. We monitored the influx and maturation of MCs by their expression of Kit, FcεRI, β7 integrin and side scatter (SSC) by flow cytometry. Influx of MC progenitors (MCps) (FcεRIlo, Kitint, β7hi, SSClo) peaks 1 day after challenges and subsides to baseline by day 7 post-challenge. The mature MMCs appear as a distinct population on day 7 and peak at day 14 with higher SSC and FcεRI expression, but lower β7 and Kit expression. A distinct transitional population is present between 1 and 7 days post-challenge. Maturation occurs more rapidly in the trachea. The resident tracheal CMC had higher SSC, FcεRI, and Kit and lower β7 integrin expression than the MMC. By histology, the MMCs follow similar kinetics to the flow cytometry-identified mature MMCs and are notably persistent for >42 days. Steroid treatment reduced inflammation and MCp influx but had no effect on established MMC. Thus changes in SSC, FcεRI, and Kit together with expression of αE/α4:β7 integrins characterizes the development of induced MMCs from MCps and distinguishes them from resident CMC in the trachea and large airways

A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis

T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25 + type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF