Role of Macrophage accumulation activates NLRP3 inflammasome induced IL-18 pathway in EoE pathogenesis

Objective Most studies implicated eosinophilic esophagitis (EoE) to the induced esophageal eosinophilia mediated inflammation and fibrosis. However, yet the initial mechanism of allergen-induced eosinophils generation is yet not understood. Our current study provides stepwise pathway operating following the interaction of allergen and antigen presenting cells to induce EoE pathogenesis. Methods We performed immunostaining, RT-PCR measure transcript levels and Masson trichrome staining for collagen accumulation. Results We show that allergen-challenge promotes induced macrophage accumulation and epithelial cells hyperplasia in esophagus. Further, we observed that NLRP3 is induced in both macrophage and epithelial cells. The NLRP3 is the source of IL-18 and we show induced levels of IL-18 in allergen challenge mice that generate tissue eosinophilia in experimental model of EoE. Further, we observed a similar induced NLRP3 in the accumulated macrophage and epithelial cells along with induced IL-18 in the esophageal biopsies of human EoE. Mechanistically, to substantiate the role of macrophages, epithelial cells, and IL-18 role in EoE pathogenesis, we experimentally induced EoE in wild type, GM-CSF−/−, IL-18−/− mice. We show a similar NLRP3 expression with no IL-18 induction in IL-18−/− mice compare to induced NLRP3 and IL-18 in wild-type and significantly reduced NLRP3 and IL-18 in GM-CSF−/− mice. The NLRP3 regulated IL-18 induction or reduction is consistent with the tissue accumulated eosinophila and promoting esophageal remodeling and fibrosis in murine model of EoE. Conclusions The findings show that epithelial cells and macrophage derived NLRP3 regulated IL-18 is critical in promoting EoE pathogenesis. Supported by NIH grant R01 AI080581