In vivo targeting of miR‐223 in experimental eosinophilic oesophagitis

Abstract

Objectives Eosinophilic oesophagitis (EoE) is characterised by oesophageal inflammation, fibrosis and dysfunction. Micro (mi)‐RNAs interfere with pro‐inflammatory and pro‐fibrotic transcriptional programs, and miR‐223 was upregulated in oesophageal mucosal biopsy specimens from EoE patients. The therapeutic potential of modulating miR‐223 expression in vivo has not been determined. We aimed to elucidate the relevance of oesophageal miR‐223 expression in an in vivo model of EoE by inhibiting miR‐223 tissue expression. Methods The expression of miR‐223 and the validated miR‐223 target insulin‐like growth factor receptor 1 (IGF1R) protein was determined in our paediatric cohort of EoE patients. A murine model of Aspergillus fumigatus‐induced EoE was employed, and oesophagi were assessed for miR‐233, IGF1R, T lymphocyte type 2 (T2) cytokine expression and eosinophil infiltration. Mice were treated with antagomirs targeting miR‐223 or resveratrol targeting its upstream regulator Midline‐1(MID‐1). Results There was an inverse relationship between an increased expression of miR‐223 and a decreased IGF1R protein concentration in biopsy specimens from EoE patients. TNF‐related apoptosis‐inducing ligand deficiency, MID‐1 inhibition and resveratrol treatment suppressed miR‐223 expression. Furthermore, inhibition of miR‐223 and treatment with resveratrol in the oesophagus resulted in an amelioration of EoE hallmark features including eosinophilic infiltration, oesophageal circumference and a reduction in T2 cytokine expression. Conclusion miR‐223 has a key role in the perpetuation of EoE hallmark features downstream of TNF‐related apoptosis‐inducing ligand and MID‐1 in an experimental model. These studies highlight a potentially critical role of miRNA function in EoE aetiology. miR‐223 expression in the oesophagus may be therapeutically modulated by resveratrol, providing a potential new therapeutic option to be explored in EoE patients for this increasingly prevalent condition.

The role of the allergist in the management of eosinophilic esophagitis

“…Consistent with both local and systemic immune mechanisms, a recent study demonstrated the local deposition of dust mite antigens in the esophageal epithelium of patients with EoE [32 & ,33 & ]. These data are consistent with animal models of EoE in which esophageal eosinophilia, T cell infiltration, and mastocytosis are driven by nasal challenge with aeroallergens such as house dust mite and aspergillus [34,35]. It should be noted that there is some controversy in the literature regarding seasonal aeroallergen effects on EoE.…”

Eosinophils Infiltration in Esophageal Muscularis Propria Induces Achalasia-like Esophageal Motility Disorder in Mice

“…The depth of eosinophil infiltration into the esophagus is related to types of respiratory antigen and the exposure procedures. Simple respiratory allergenic (such as dog, cat, cockroach, dust mite and A. fumigatus) stimulation, lasting for 21–28 days, could promote the infiltration of eosinophil, mainly in the epithelium [ 12 , 25 ]. However, if the mice were sensitized by intraperitoneal injection of OVA and then exposed to OVA via respiratory tract for 24 days, the eosinophil infiltrated more deeply, with most of the eosinophils infiltrated into the mucosa and submucosa [ 15 ].…”

“…Since AC-like dysmotility can also be seen in some eosinophilic esophagitis (EoE) patients [ 10 ], using an animal model of EoE as a surrogate is a potential solution. Among various methods to establish an animal model of EoE [ 11 , 12 , 13 , 14 ], the respiratory tract antigen, such as ovalbumin (OVA), exposure is simple, low cost and easy to control experimental conditions [ 15 ]. However, to the best of our knowledge, the depth of the eosinophil infiltration is mainly in squamous-epithelial, lamina propria and submucosa of esophagus in the mouse models listed above [ 11 , 14 , 15 ], which is not consistent with previous pathological finding in AC.…”