TSLP, IL-9-producing mucosal mast cells, and allergic inflammation

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The development and pathogenesis of atopic dermatitis is thought to be the first step in the path to develop other allergic diseases, such as asthma; the disease progression also known as the “atopic march”. Current knowledge cannot explain why allergic inflammation is restricted to one tissue in some individuals, while it progresses to involve additional tissues in other individuals. It is increasingly evident that the mechanisms of disease progression are far more complex than allergic sensitization. TSLP is necessary and sufficient for the atopic march in mouse models3-5, however, the mechanisms underpinnings TSLP's contribution to allergic disease progression is not clear. We recently published our findings describing a novel population of intestinal mucosal mast cells (MMC9) in mice that produce high levels of IL-9, IL-13, and mast cell proteases 1 (chymase) and 6 (tryptase)6. Our published and unpublished studies demonstrate: (1) MMC9s are scarce in immunologically naïve mice, but accumulate in the gut of mice with TSLP-induced AD following ingestion of food antigens; (2) MMC9 are found in the lungs of AD mice following ingestion of food antigens and their presence is associated with airway inflammation characteristic of asthma; (3) ablation of MMC9s results in attenuated CD4+TH2 immune responses and resistance to develop asthma-like airway inflammation; (4) MMC9-like cells are present in humans and expression levels of MMC9 markers are associated with co-morbid allergic disease; (5) IL-33 expression is induced in mouse intestinal epithelium following ingestion of food antigens; and (6) IL-33 induces purified murine MMC9s to produce higher levels of IL-9 and IL-13. Collectively, these exciting findings suggest that MMC9 induction in GI tract may serve as a key cellular checkpoint that bridges TSLP production in the skin to asthma development in the lung, i.e. allergic disease progression. Our central hypothesis is that epidermal TSLP-initiated CD4+TH2 immune responses drive MMC9 development in the gastrointestinal (GI) tract and that intestinal epithelial-derived IL-33 (induced by ingested food antigens) then amplifies MMC9 function and airway MMC9 accumulation to promote allergic asthma. This hypothesis is highly clinically relevant. This application will have significant public health impact. Through the proposed aims, we will (1) elucidate the mechanisms that promote the development and expansion of MMC9 cells; (2) elucidate the role of MMC9 in the pathogenesis of co-morbid allergic disease; (4) delineate immunologic biomarkers that predict disease progression from AD to asthma; and (4) provide mechanistic data that will enable the design of therapeutic interventions to prevent the progression of allergic disorders.