Allergen-induced NLRP3/caspase1/IL-18 signaling initiate eosinophilic esophagitis and respective inhibitors protect disease pathogenesis

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.

Vasoactive Intestinal Peptide Receptor, CRTH2, Antagonist Treatment Improves Eosinophil and Mast Cell-Mediated Esophageal Remodeling and Motility Dysfunction in Eosinophilic Esophagitis

“…Age-and sex-matched mice (6-8 weeks) were used in all trials. EoE was induced using similar methods as in the earlier experiments [40,41]. Briefly, mice were anesthetized with a light dose of isoflurane (Iso-Flo; Abbott Laboratories, North Chicago, IL, USA), then administered 100 µg Aspergillus fumigatus (Greer Laboratories, Lenoir, NC, USA) in 50 µL normal saline (or 50 µL normal saline alone for control mice) intranasally three times weekly for three weeks while in a supine position.…”