Collison Adam M, Sokulsky Leon A, Nightingale Scott, Percival Elizabeth, LeFevre Anna, Meredith Joseph, Krauss Sybille, Foster Paul S, Mattes Joerg
Experimental and Translational Respiratory Medicine Group Newcastle NSW Australia.
Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia.
Clin Transl Immunology. 2020 Nov 23;9(11):e1210. doi: 10.1002/cti2.1210. eCollection 2020.
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 has not been determined. We aimed to elucidate the relevance of oesophageal miR-223 expression in an model of EoE by inhibiting miR-223 tissue expression.
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 -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).
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.
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.
嗜酸性粒细胞性食管炎（EoE）的特征为食管炎症、纤维化及功能障碍。微小（mi）-RNA可干扰促炎和促纤维化转录程序，且在EoE患者的食管黏膜活检标本中miR-223表达上调。调节miR-223表达的治疗潜力尚未确定。我们旨在通过抑制miR-223的组织表达来阐明食管miR-223表达在EoE模型中的相关性。
在我们的EoE患儿队列中测定miR-223及经验证的miR-223靶标胰岛素样生长因子受体1（IGF1R）蛋白的表达。采用肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的EoE小鼠模型，评估食管中miR-233、IGF1R、2型T淋巴细胞（T2）细胞因子表达及嗜酸性粒细胞浸润情况。用靶向miR-223的反义寡核苷酸或靶向其上游调节因子中线-1（MID-1）的白藜芦醇处理小鼠。
EoE患者活检标本中miR-223表达增加与IGF1R蛋白浓度降低呈负相关。TRAIL缺陷、MID-1抑制及白藜芦醇处理均可抑制miR-223表达。此外，食管中miR-223的抑制及白藜芦醇处理可改善EoE的标志性特征，包括嗜酸性粒细胞浸润、食管周长及T2细胞因子表达降低。
在实验模型中，miR-223在TRAIL和MID-1下游的EoE标志性特征持续存在中起关键作用。这些研究突出了miRNA功能在EoE病因学中潜在的关键作用。白藜芦醇可对食管中miR-223的表达进行治疗性调节，为这种日益普遍的疾病的EoE患者提供了一个有待探索的潜在新治疗选择。
