In vivo targeting of miR‐223 in experimental eosinophilic oesophagitis

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.