Costa Maxime, Pottier Muriel, Jacob Marie, Zarnitzky Pauline, Segain Benjamin, Figeac Martin, Sebda Shéhérazade, Leprêtre Frédéric, Meresse Bertrand, Demaret Julie, Foligné Benoit, Standaert Annie, Bertin Benjamin
Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France.
Plateau de Génomique Fonctionnelle et Structurale, CHU Lille, Univ. Lille, Lille France.
J Leukoc Biol. 2025 Apr 23;117(4). doi: 10.1093/jleuko/qiaf004.
The gastrointestinal tract is a remarkable example of complex biology, with a constant dialogue between the intestinal epithelium, in close contact with the microbiota, and the immune cells that protect the gut from infection. Organoids have revolutionized our approach to modeling the intestinal cellular compartment and have opened new avenues for unraveling the mechanisms involved in intestinal homeostasis and chronic pathogenesis, such as inflammatory bowel disease. To date, few models have been established to explore the role of the colon, which is, however, the main site of inflammation in ulcerative colitis. Here, we used conditioned media produced by colon organoids from mice or humans (control patients and patients with ulcerative colitis) to investigate the relationship between macrophages and the colon epithelium. We addressed transcriptomic profiles of organoid conditioned media-stimulated bone marrow-derived macrophages and found that these cells exhibited a unique anti-inflammatory signature distinct from that of conventional in vitro IL-4/IL-13 M2-differentiated macrophages. In addition, organoid conditioned media induced a clear CD5 antigen-like-mediated immunoregulatory effect characterized by a significant reduction in lipopolysaccharide-induced inducible nitric oxide synthase expression. In line, organoid conditioned media from human colons inhibited lipopolysaccharide-dependent inflammatory cytokine expression in human monocyte-derived macrophages. Interestingly, the inflammatory marker CD68 was reduced by organoid conditioned media from control patients but not from patients with ulcerative colitis, suggesting epithelial dysfunction in patients with ulcerative colitis. Our results report new regulatory mechanisms in the colon and highlight the importance of developing new in vitro models to better characterize the relationship between the intestinal epithelium and immune mucosal cells.
胃肠道是复杂生物学的一个显著例子，肠道上皮与微生物群紧密接触，并与保护肠道免受感染的免疫细胞之间持续进行对话。类器官彻底改变了我们对肠道细胞区室建模的方法，并为揭示肠道稳态和慢性发病机制（如炎症性肠病）所涉及的机制开辟了新途径。迄今为止，很少有模型被建立来探索结肠的作用，然而结肠却是溃疡性结肠炎炎症的主要部位。在这里，我们使用来自小鼠或人类（对照患者和溃疡性结肠炎患者）的结肠类器官产生的条件培养基来研究巨噬细胞与结肠上皮之间的关系。我们分析了类器官条件培养基刺激的骨髓来源巨噬细胞的转录组谱，发现这些细胞表现出一种独特的抗炎特征，不同于传统体外IL-4/IL-13诱导分化的M2巨噬细胞。此外，类器官条件培养基诱导了一种明显的CD5抗原样介导的免疫调节作用，其特征是脂多糖诱导的诱导型一氧化氮合酶表达显著降低。同样，来自人类结肠的类器官条件培养基抑制了人类单核细胞来源巨噬细胞中脂多糖依赖性炎症细胞因子的表达。有趣的是，对照患者的类器官条件培养基降低了炎症标志物CD68，但溃疡性结肠炎患者的类器官条件培养基则没有，这表明溃疡性结肠炎患者存在上皮功能障碍。我们的结果报道了结肠中的新调节机制，并强调了开发新的体外模型以更好地表征肠道上皮与免疫黏膜细胞之间关系的重要性。
