Iannucci Andrea, Colella Marco, Quiroga Macarena, Frascatani Rachele, Tomassini Lorenzo, Maresca Claudia, Franzè Eleonora, Laudisi Federica, Sica Giuseppe, Marafini Irene, Michienzi Alessandro, Zanoni Ivan, Monteleone Giovanni, Monteleone Ivan
Department of Biomedicine and Prevention University of Rome "Tor Vergata" Rome Italy.
Department of Systems Medicine University of Rome "Tor Vergata" Rome Italy.
MedComm (2020). 2025 Jun 6;6(6):e70212. doi: 10.1002/mco2.70212. eCollection 2025 Jun.
The gut virome is a complex community that exists in equilibrium with the host. Disruptions of this balance could drive the development of inflammatory diseases, such as inflammatory bowel disease (IBD). RNA editing, particularly A-to-I editing by ADAR1, prevents the excessive immune response to viral double strand (ds) RNA. Failure of RNA editing may sustain inflammation and this study explore the role of ADAR1 in IBD. ADAR1 was analyzed in IBD patients and healthy controls (CTR) using western blotting and qPCR. Colonic epithelial cells (HCEC-1CT), ex vivo organ cultures, and colonic organoids were treated poly I:C after ADAR1 silencing with an antisense oligonucleotide (AS). Inflammatory pathways and PANoptosome were measured by western blotting, flow cytometry, and ELISA. The role of ADAR1 was also studied in DSS-colitis model. ADAR1 was significantly reduced in the inflamed epithelium of ulcerative colitis (UC) gut samples. ADAR1 silencing in HCEC-1CT, ex vivo organ cultures or colonic organoids strongly increases the immune response to poly I:C and leads to activation of inflammatory pathways and PANoptosis. Inhibition of gut ADAR1 expression during DSS-colitis exacerbated gut inflammation. JAK inhibition or AhR activation mitigated the immune response that follows ADAR1 silencing. These data suggest that ADAR1 could be involved in IBD inflammation.
肠道病毒组是一个与宿主处于平衡状态的复杂群落。这种平衡的破坏可能会推动炎症性疾病的发展，如炎症性肠病（IBD）。RNA编辑，特别是ADAR1介导的A到I编辑，可防止对病毒双链（ds）RNA产生过度免疫反应。RNA编辑功能的缺失可能会持续引发炎症，本研究旨在探索ADAR1在IBD中的作用。采用蛋白质免疫印迹法和定量聚合酶链反应（qPCR）对IBD患者和健康对照（CTR）进行ADAR1分析。在用反义寡核苷酸（AS）沉默ADAR1后，对结肠上皮细胞（HCEC-1CT）、离体器官培养物和结肠类器官进行聚肌胞苷酸（poly I:C）处理。通过蛋白质免疫印迹法、流式细胞术和酶联免疫吸附测定（ELISA）检测炎症信号通路和PAN小体。还在葡聚糖硫酸钠（DSS）诱导的结肠炎模型中研究了ADAR1的作用。在溃疡性结肠炎（UC）肠道样本的炎症上皮中，ADAR1显著减少。在HCEC-1CT、离体器官培养物或结肠类器官中沉默ADAR1会强烈增强对poly I:C的免疫反应，并导致炎症信号通路的激活和PAN凋亡。在DSS诱导的结肠炎期间抑制肠道ADAR1的表达会加剧肠道炎症。抑制Janus激酶（JAK）或激活芳烃受体（AhR）可减轻ADAR1沉默后的免疫反应。这些数据表明，ADAR1可能与IBD炎症有关。
