2. Academic Validation
  3. Allergen-induced NLRP3/caspase1/IL-18 signaling initiate eosinophilic esophagitis and respective inhibitors protect disease pathogenesis

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.
Chandra Sekhar Yadavalli 1,  Sathisha Upparahalli Venkateshaiah 1,  Sandeep Kumar 1 2,  Hemanth Kumar Kandikattu 1,  Lokanatha Oruganti 1 3,  Chandra Sekhar Kathera 1,  Anil Mishra 4
Affiliations

Affiliations

  • 1 John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA, USA.
  • 2 Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
  • 3 Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA.
  • 4 John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA, USA. amishra@tulane.edu.
PMID: 37524769 DOI: 10.1038/s42003-023-05130-4
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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