Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
JCI Insight. 2023 Sep 8;8(17):e172143. doi: 10.1172/jci.insight.172143.
Eosinophilic esophagitis (EoE) is a chronic gastrointestinal disorder characterized by food antigen-driven eosinophilic inflammation and hyperproliferation of esophageal mucosa. By utilizing a large-scale, proteomic screen of esophageal biopsies, we aimed to uncover molecular drivers of the disease. Proteomic analysis by liquid chromatography-tandem mass spectrometry identified 402 differentially expressed proteins (DEPs) that correlated with the EoE transcriptome. Immune cell-related proteins were among the most highly upregulated DEPs in EoE compared with controls, whereas proteins linked to epithelial differentiation were primarily downregulated. Notably, in the inflamed esophageal tissue, all 6 subunits of the minichromosome maintenance (MCM) complex, a DNA helicase essential for genomic DNA replication, were significantly upregulated at the gene and protein levels. Furthermore, treating esophageal epithelial cells with a known inhibitor of the MCM complex (ciprofloxacin) blocked esophageal epithelial proliferation. In a murine model of EoE driven by overexpression of IL-13, ciprofloxacin treatment decreased basal zone thickness and reduced dilated intercellular spaces by blocking the transition of epithelial cells through the S-phase of the cell cycle. Collectively, a broad-spectrum proteomic screen has identified the involvement of the MCM complex in EoE and has highlighted MCM inhibitors as potential therapeutic agents for the disease.
嗜酸性食管炎（EoE）是一种慢性胃肠道疾病，其特征是食物抗原驱动的嗜酸性粒细胞炎症和食管黏膜过度增生。通过利用大规模的食管活检蛋白质组学筛选，我们旨在揭示疾病的分子驱动因素。液相色谱-串联质谱的蛋白质组学分析鉴定出 402 个与 EoE 转录组相关的差异表达蛋白（DEPs）。与对照组相比，EoE 中免疫细胞相关蛋白的上调最为明显，而与上皮分化相关的蛋白则主要下调。值得注意的是，在炎症性食管组织中，微染色体维持（MCM）复合物的所有 6 个亚基，一种对基因组 DNA 复制至关重要的 DNA 解旋酶，在基因和蛋白水平均显著上调。此外，用已知的 MCM 复合物抑制剂（环丙沙星）处理食管上皮细胞可阻断食管上皮细胞增殖。在 IL-13 过表达驱动的 EoE 小鼠模型中，环丙沙星治疗通过阻断上皮细胞通过细胞周期 S 期，减少基底区厚度并减少扩张的细胞间隙，从而降低疾病严重程度。总的来说，广泛的蛋白质组学筛选已经确定了 MCM 复合物在 EoE 中的参与，并强调了 MCM 抑制剂作为该疾病潜在治疗药物的潜力。
