Allergen‐induced interleukin‐18 promotes experimental eosinophilic oesophagitis in mice

Abstract

Elevated levels of IL-18 have been reported in a number of allergic diseases. We recently reported that IL-18 in the blood and IL-18Rα mRNA in the oesophagus are induced during human eosinophilic oesophagitis (EoE). Additionally, we earlier showed that iNKT cells are critical to EoE pathogenesis; however, the mechanism of iNKT cell activation in EoE is not well understood. Therefore, the current study focused on the hypothesis that allergen-induced IL-18 may have an important role in iNKT cell-mediated EoE pathogenesis. We first validated the human EoE findings of IL-18 in experimental EoE by examining blood levels of IL-18 and oesophageal IL-18Rα mRNA levels in aeroallergen- and food allergen-induced experimental mouse models of EoE. We demonstrate that blood IL-18 protein and oesophageal IL-18Rα mRNA are induced in the mouse model of EoE and that IL-18Rα is expressed by iNKT cells in the oesophagus. Intranasal delivery of rIL-18 induced both mast cells and eosinophilic inflammation in the oesophagus in a time- and dose-dependent manner. To establish the significance of IL-18 in EoE pathogenesis, we examined DOX-inducible rtTA-CC10-IL-18 bitransgenic mice that induce IL-18 protein expression in the oesophagus. Our analysis indicated that induction of IL-18 in these mice resulted in the development of many of the characteristics of EoE, including oesophageal intraepithelial eosinophilia, increased mast cells, oesophageal remodelling and fibrosis. The current study provides evidence that IL-18 may induce iNKT cell activation to release the eosinophil activating cytokine IL-5, as IL-5-deficient mice and iNKT cell-deficient (CD1d null) mice do not induce EoE in response to intranasal IL-18 challenge. Taken together, these findings provide evidence that allergen-induced IL-18 has a significant role in promoting IL-5- and iNKT-dependent EoE pathogenesis.

Role of interleukin-18 in the pathophysiology of allergic diseases

“…Our early results showed increased levels of the IL-18 receptor transcript in humans [139]. We have recently demonstrated induction of IL-18 and its receptor in a mouse model of eosinophilic esophagitis (EoE) [91]. We have also demonstrated correlations between IL-18 and eosinophilia in human EoE patients in addition to the previously mentioned results of iNKT cells [90].…”

“…The data from our group indicates that direct exposure of IL-18 to invariant NKT (iNKT) cells in vitro releases eosinophilia-promoting cytokines like IL-4, Il-5 and IL-13, and promotes eosinophilic inflammation in tissue [90]. Additionally, we showed that transgenic mice overexpressing IL-18 are capable of promoting pulmonary and gastrointestinal eosinophilic disorders presumably via this iNKT activation [91]. …”

Role of Vasoactive Intestinal Peptide in Promoting the Pathogenesis of Eosinophilic Esophagitis (EoE)

“…The Tulane Institutional Animal Care and Use Committee approved the animal protocols. Experimental EoE in mice was induced using methods described previously 3 , 4 , 5 that were used in accordance with National Institutes of Health guidelines. In brief, mice were lightly anesthetized with isoflurane (Iso-Flo; Abbott Laboratories, North Chicago, IL), and 100 μg of Aspergillus fumigatus (Greer Laboratories, Lenoir, NC) in 50 μL normal saline or 50 μL normal saline alone was given intranasally using a micropipette with the mouse held in the supine position 3 times/wk for 3 weeks.…”

Synergy of Interleukin (IL)-5 and IL-18 in eosinophil mediated pathogenesis of allergic diseases

“…We previously reported that IL-18 induce iNKT cell activation to release the eosinophil activating cytokine IL-5, as IL-5-deficient mice and iNKT cell-deficient (CD1d null) mice do not induce EoE in response to intranasal IL-18 challenge. Thus allergen-induced IL-18 has a significant role in promoting IL-5 and iNKT dependent EoE pathogenesis in mice [102]. IL-18 overexpression induces Th1, Th2 cytokine-mediated airway inflammation in mice with an increase in IFNγ, IL-13, eotaxin levels and CD4 + T cells in ova sensitized mice [103].…”