- Title
- In vivo targeting of miR-223 in experimental eosinophilic oesophagitis
- Creator
- Collison, Adam M.; Sokulsky, Leon A.; Nightingale, Scott; Percival, Elizabeth; LeFevre, Anna; Meredith, Joseph; Krauss, Sybille; Foster, Paul S.; Mattes, Joerg
- Relation
- NHMRC.1011153 ttp://purl.org/au-research/grants/nhmrc/1011153 & 1060074 http://purl.org/au-research/grants/nhmrc/1060074
- Relation
- Clinical & Translational Immunology Vol. 9, Issue 11, no. e1210
- Publisher Link
- http://dx.doi.org/10.1002/cti2.1210
- Publisher
- Wiley-Blackwell
- Resource Type
- journal article
- Date
- 2020
- Description
- 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.
- Subject
- eosinophilic oesophagitis; microRNA; midline-1; resveratrol
- Identifier
- http://hdl.handle.net/1959.13/1441930
- Identifier
- uon:41570
- Identifier
- ISSN:2050-0068
- Language
- eng
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