| Summary: | Abstract The current report describes a stepwise mechanistic pathway of NLRP3/caspase1/IL-18-regulated immune responses operational in eosinophilic esophagitis (EoE). We show that esophageal epithelial cells and macrophage-derived NLRP3 regulated IL-18 initiate the disease and induced IL-5 facilitates eosinophil growth and survival. We also found that A. fumigatus-exposed IL-18−/− mice or IL-18-neutralized mice are protected from EoE induction. Most importantly, we present that intravascular rIL-18 delivery to ΔdblGATA mice and CD2-IL-5 mice show the development of EoE characteristics feature like degranulated and intraepithelial eosinophils, basal cell hyperplasia, remodeling and fibrosis. Similarly, we show an induced NLRP3-caspase1-regulated IL-18 pathway is also operational in human EoE. Lastly, we present the evidence that inhibitors of NLRP3 and caspase-1 (MCC950, BHB, and VX-765) protect A. fumigatus- and corn-extract-induced EoE pathogenesis. In conclusion, the current study provides a new understanding by implicating NLRP3/caspase1-regulated IL-18 pathway in EoE pathogenesis. The study has the clinical significance and novel therapeutic strategy, which depletes only IL-18-responsive pathogenic eosinophils, not naïve IL-5-generated eosinophils critical for maintaining innate immunity.
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