Seco-Cervera Marta, Gisbert-Ferrándiz Laura, Macias-Ceja Dulce C, Ortiz-Masiá Dolores, Cosín-Roger Jesús, Bauset Cristina, Heras-Moran Begoña, Navarro-Vicente Francisco, Civera-Barrachina Maria, Ibáñez-Cabellos José Santiago, Calatayud Sara, Barrachina María D
Hospital Universitario Dr. Peset, FISABIO, Valencia, Spain.
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
PLoS One. 2025 Aug 11;20(8):e0329685. doi: 10.1371/journal.pone.0329685. eCollection 2025.
Epigenetics has emerged as a modulator of inflammation-related diseases and changes in miRNA expression have been associated with regional location, inflamed mucosa and disease activity in Crohn´s disease (CD). We analyse here the differential ileal miRNA expression in fibrotic tissue from patients with complicated CD and its relevance in inflammation and fibrosis. A miRNA sequencing analysis has been performed in ileal surgical resections from both patients with complicated CD and control subjects. The correlation analysis of data with an mRNA seq study performed in the same samples pointed to hsa-miR-378a-3p as an epigenetic regulator of inflammatory and fibrotic genes. Results demonstrate a significant diminution in the expression of miR-378a-3p in three different inflammatory conditions: ileum from complicated CD patients, intestine from DSS (Dextran Sulfate Sodium)-treated mice and macrophages polarized towards an M1 phenotype. Treatment with miR-378a-3p mimics failed to prevent inflammation and fibrosis in DSS-treated mice while it increased the expression of several cytokines and chemokines in both murine intestine and M1 macrophages. In conclusion, our study shows the downregulation of miR-378a-3p expression in human and murine intestinal inflammation and demonstrates that restoring the intestinal miR-378a-3p levels did not prevent inflammation and fibrosis in murine chronic colitis while intensified the expression of inflammatory and fibrotic markers.
表观遗传学已成为炎症相关疾病的调节因子，且微小RNA（miRNA）表达的变化与克罗恩病（CD）的病变部位、炎症黏膜及疾病活动相关。我们在此分析复杂型CD患者纤维化组织中回肠miRNA的差异表达及其在炎症和纤维化中的相关性。对复杂型CD患者和对照受试者的回肠手术切除组织进行了miRNA测序分析。对相同样本进行的mRNA测序研究的数据相关性分析表明，hsa-miR-378a-3p是炎症和纤维化基因的表观遗传调节因子。结果显示，在三种不同的炎症状态下，miR-378a-3p的表达显著降低：复杂型CD患者的回肠、硫酸葡聚糖钠（DSS）处理小鼠的肠道以及极化至M1表型的巨噬细胞。用miR-378a-3p模拟物处理未能预防DSS处理小鼠的炎症和纤维化，同时却增加了小鼠肠道和M1巨噬细胞中几种细胞因子和趋化因子的表达。总之，我们的研究表明miR-378a-3p在人和小鼠肠道炎症中表达下调，并证明恢复肠道miR-378a-3p水平并不能预防小鼠慢性结肠炎的炎症和纤维化，反而会增强炎症和纤维化标志物的表达。
