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

Commun Biol. 2023 Jul 31;6(1):763. doi: 10.1038/s42003-023-05130-4.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allergens / adverse effects
  • Animals
  • Eosinophilic Esophagitis* / drug therapy
  • Eosinophilic Esophagitis* / pathology
  • Humans
  • Interleukin-18 / adverse effects
  • Interleukin-5 / adverse effects
  • Interleukin-5 / metabolism
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics


  • Allergens
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Interleukin-5
  • Interleukin-18