Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection.
Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection.
复制标题
巨噬细胞上皮重编程是分枝杆菌肉芽肿的基础并促进感染。
DOI：
10.1016/j.immuni.2016.09.014
复制
发表时间：
2016-10-18
期刊：
影响因子：
32.4
通讯作者：
Tobin DM
中科院分区：
文献类型：
--
作者：
Cronan MR;Beerman RW;Rosenberg AF;Saelens JW;Johnson MG;Oehlers SH;Sisk DM;Jurcic Smith KL;Medvitz NA;Miller SE;Trinh LA;Fraser SE;Madden JF;Turner J;Stout JE;Lee S;Tobin DM
人类结核分枝杆菌感染触发肉芽肿的形成，肉芽肿是结核病的中心结构，是紧密组织的免疫细胞聚集体。感染和未感染的巨噬细胞相互交错，呈现出改变的扁平外观。虽然病理学家描述这些变化超过世纪，分子和细胞的程序，这种转变是不清楚的。在这里，使用斑马鱼-海洋分枝杆菌模型，我们发现分枝杆菌肉芽肿的形成伴随着巨噬细胞诱导典型的上皮分子和结构。我们确定了基本的巨噬细胞重编程事件，平行E-钙粘蛋白依赖性间充质上皮细胞的转变。巨噬细胞特异性破坏E-钙粘蛋白功能导致肉芽肿形成紊乱，增强免疫细胞的访问，减少细菌负荷和增加宿主存活，这表明肉芽肿也可以起到细菌保护作用。结核病患者的肉芽肿巨噬细胞也发生了类似的转化。因此，在分枝杆菌感染期间，肉芽肿巨噬细胞被上皮模块广泛地重编程，并且这种重编程改变了感染的轨迹和相关的免疫应答。
Mycobacterium tuberculosis infection in humans triggers formation of granulomas, tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. Here, using the zebrafish-Mycobacterium marinum model, we found that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. We identified fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function resulted in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. Granuloma macrophages in humans with tuberculosis were similarly transformed. Thus, during mycobacterial infection, granuloma macrophages are broadly reprogrammed by epithelial modules, and this reprogramming alters the trajectory of infection and the associated immune response.