In vivo targeting of miR-223 in experimental eosinophilic oesophagitis

Adam M Collison; Leon A Sokulsky; Scott Nightingale; Elizabeth Percival; Anna LeFevre; Joseph Meredith; Sybille Krauss; Paul S Foster; Joerg Mattes

doi:10.1002/cti2.1210

In vivo targeting of miR-223 in experimental eosinophilic oesophagitis

Clin Transl Immunology. 2020 Nov 23;9(11):e1210. doi: 10.1002/cti2.1210. eCollection 2020.

Authors

Adam M Collison^{1

2}, Leon A Sokulsky^{1

2

3}, Scott Nightingale^{2

4}, Elizabeth Percival^{1

2}, Anna LeFevre², Joseph Meredith², Sybille Krauss⁵, Paul S Foster³, Joerg Mattes^{1

2

6}

Affiliations

¹ Experimental and Translational Respiratory Medicine Group Newcastle NSW Australia.
² Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia.
³ Priority Research Centre for Healthy Lungs The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia.
⁴ Paediatric Gastroenterology Department John Hunter Children's Hospital Newcastle NSW Australia.
⁵ Faculty IV: School of Science and Technology Institute of Biology Department Human Biology/Neurobiology University of Siegen Siegen Germany.
⁶ Paediatric Respiratory & Sleep Medicine Department Newcastle Children's Hospital Kaleidoscope Newcastle NSW Australia.

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.

Keywords: Midline‐1; eosinophilic oesophagitis; microRNA; resveratrol.