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Allergen-induced interleukin-18 promotes experimental eosinophilic oesophagitis in mice.

Dutt P, Shukla JS, Ventateshaiah SU, Mariswamy SJ, Mattner J, Shukla A, Mishra A - Immunol. Cell Biol. (2015)

Bottom Line: Elevated levels of interleukin (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).Intranasal delivery of rIL-18 induced both mast cells and eosinophilic inflammation in the oesophagus in a time- and dose-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Section of Department of Medicine, Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA.

ABSTRACT
Elevated levels of interleukin (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 invariant natural killer T (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 ) 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.

No MeSH data available.


Related in: MedlinePlus

Oesophageal fibrosis is induced in IL-18 overexpressed miceThe characteristic features of EoE oesophageal fibrosis were examined by Masson’s trichrome staining for the accumulation of collagen in the oesophageal tissue sections. A significantly increase of collagen in the lamina propria, epithelial mucosa and muscularis mucosa of 3 weeks DOX exposed mice were detected compared to the baseline collagen in the lamina propria of no-DOX mice (A, B., magnification 400×). Morphometric analysis of lamina propria collagen thickness/mm2 is shown (C). The data show the means ± S.D pooled from 3 experiments, (4-mice/group/treatment/experiments; total mice=12/group). EP, Epithelium; LP, Lamina propria; MS, Muscularis Mucosa; LU, Lumen.
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Figure 5: Oesophageal fibrosis is induced in IL-18 overexpressed miceThe characteristic features of EoE oesophageal fibrosis were examined by Masson’s trichrome staining for the accumulation of collagen in the oesophageal tissue sections. A significantly increase of collagen in the lamina propria, epithelial mucosa and muscularis mucosa of 3 weeks DOX exposed mice were detected compared to the baseline collagen in the lamina propria of no-DOX mice (A, B., magnification 400×). Morphometric analysis of lamina propria collagen thickness/mm2 is shown (C). The data show the means ± S.D pooled from 3 experiments, (4-mice/group/treatment/experiments; total mice=12/group). EP, Epithelium; LP, Lamina propria; MS, Muscularis Mucosa; LU, Lumen.

Mentions: Chronic tissue eosinophilia and mast cell inflammation are implicated in promoting oesophageal remodelling and fibrosis in EoE. Therefore, we were next interested in establishing that IL-18-induced eosinophilic and mast cell inflammation promote oesophageal fibrosis in DOX-inducible IL-18 bitransgenic mice. Accordingly, oesophageal tissue sections of no-DOX and DOX-exposed IL-18 transgenic mice were stained with Masson’s trichrome for collagen accumulation in the epithelial mucosa and lamina propria to detect oesophageal fibrosis. Oesophageal tissue sections from no-DOX and DOX-exposed IL-18 bitransgenic mice were analysed by trichrome staining for collagen accumulation in the epithelial mucosa and for fibrosis in the lamina propria. Analysis of oesophageal sections demonstrated normal epithelial and muscularis mucosa and lamina propria with organised, thin sub-epithelial trichrome material in the no-DOX mice (Figure 5 A). By contrast, the oesophagus of DOX-exposed IL-18 bitransgenic mice showed collagen induction and expansion of connective tissue in the oesophageal epithelial mucosa, lamina propria and muscularis mucosa (Figure 5 B). Interestingly, we observed that most DOX-treated IL-18 transgenic mice had shorter lumens compare with no-DOX mice. A semi-quantitative analysis performed using digital morphometry (Luminera Corporation, Infinity Analyze 6.1.0) indicated ~ 3-fold increase of lamina propria collagen thickness in DOX-exposed IL-18 bitransgenic mice. (Figure 5 C). The lamina propria collagen thickness in the oesophagus of DOX-exposed IL-18 transgenic mice was 12.2 ± 4.2/mm2 compared with 3.3 ± 1.3/mm2 in no-DOX IL-18 transgenic mice The data are expressed as the mean ± SD, mice = 12/group.


Allergen-induced interleukin-18 promotes experimental eosinophilic oesophagitis in mice.

Dutt P, Shukla JS, Ventateshaiah SU, Mariswamy SJ, Mattner J, Shukla A, Mishra A - Immunol. Cell Biol. (2015)

Oesophageal fibrosis is induced in IL-18 overexpressed miceThe characteristic features of EoE oesophageal fibrosis were examined by Masson’s trichrome staining for the accumulation of collagen in the oesophageal tissue sections. A significantly increase of collagen in the lamina propria, epithelial mucosa and muscularis mucosa of 3 weeks DOX exposed mice were detected compared to the baseline collagen in the lamina propria of no-DOX mice (A, B., magnification 400×). Morphometric analysis of lamina propria collagen thickness/mm2 is shown (C). The data show the means ± S.D pooled from 3 experiments, (4-mice/group/treatment/experiments; total mice=12/group). EP, Epithelium; LP, Lamina propria; MS, Muscularis Mucosa; LU, Lumen.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581894&req=5

Figure 5: Oesophageal fibrosis is induced in IL-18 overexpressed miceThe characteristic features of EoE oesophageal fibrosis were examined by Masson’s trichrome staining for the accumulation of collagen in the oesophageal tissue sections. A significantly increase of collagen in the lamina propria, epithelial mucosa and muscularis mucosa of 3 weeks DOX exposed mice were detected compared to the baseline collagen in the lamina propria of no-DOX mice (A, B., magnification 400×). Morphometric analysis of lamina propria collagen thickness/mm2 is shown (C). The data show the means ± S.D pooled from 3 experiments, (4-mice/group/treatment/experiments; total mice=12/group). EP, Epithelium; LP, Lamina propria; MS, Muscularis Mucosa; LU, Lumen.
Mentions: Chronic tissue eosinophilia and mast cell inflammation are implicated in promoting oesophageal remodelling and fibrosis in EoE. Therefore, we were next interested in establishing that IL-18-induced eosinophilic and mast cell inflammation promote oesophageal fibrosis in DOX-inducible IL-18 bitransgenic mice. Accordingly, oesophageal tissue sections of no-DOX and DOX-exposed IL-18 transgenic mice were stained with Masson’s trichrome for collagen accumulation in the epithelial mucosa and lamina propria to detect oesophageal fibrosis. Oesophageal tissue sections from no-DOX and DOX-exposed IL-18 bitransgenic mice were analysed by trichrome staining for collagen accumulation in the epithelial mucosa and for fibrosis in the lamina propria. Analysis of oesophageal sections demonstrated normal epithelial and muscularis mucosa and lamina propria with organised, thin sub-epithelial trichrome material in the no-DOX mice (Figure 5 A). By contrast, the oesophagus of DOX-exposed IL-18 bitransgenic mice showed collagen induction and expansion of connective tissue in the oesophageal epithelial mucosa, lamina propria and muscularis mucosa (Figure 5 B). Interestingly, we observed that most DOX-treated IL-18 transgenic mice had shorter lumens compare with no-DOX mice. A semi-quantitative analysis performed using digital morphometry (Luminera Corporation, Infinity Analyze 6.1.0) indicated ~ 3-fold increase of lamina propria collagen thickness in DOX-exposed IL-18 bitransgenic mice. (Figure 5 C). The lamina propria collagen thickness in the oesophagus of DOX-exposed IL-18 transgenic mice was 12.2 ± 4.2/mm2 compared with 3.3 ± 1.3/mm2 in no-DOX IL-18 transgenic mice The data are expressed as the mean ± SD, mice = 12/group.

Bottom Line: Elevated levels of interleukin (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).Intranasal delivery of rIL-18 induced both mast cells and eosinophilic inflammation in the oesophagus in a time- and dose-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Section of Department of Medicine, Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA.

ABSTRACT
Elevated levels of interleukin (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 invariant natural killer T (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 ) 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.

No MeSH data available.


Related in: MedlinePlus