Iliopoulou Lida, Tzaferis Christos, Prados Alejandro, Roumelioti Fani, Koliaraki Vasiliki, Kollias George
Institute for Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain.
Nat Commun. 2025 Mar 28;16(1):3023. doi: 10.1038/s41467-025-57570-7.
Crohn's disease (CD) is a persistent inflammatory disorder primarily affecting the terminal ileum. The Tnf mice, which spontaneously develop CD-like ileitis due to TNF overexpression, represent a faithful model of the human disease. Here, via single-cell RNA sequencing in Tnf mice, we show that murine TNF-dependent ileitis is characterized by cell expansion in tertiary lymphoid organs (TLO), T cell effector reprogramming, and accumulation of activated macrophages in the submucosal granulomas. Within the stromal cell compartment, fibroblast subsets (telocytes, trophocytes, PdgfraCd81 cells) are less abundant while lymphatic endothelial cells (LEC) and fibroblastic reticular cells (FRC) show relative expansion compared to the wild type. All three fibroblast subsets show strong pro-inflammatory signature. TNFR1 loss or gain of function experiments in specific fibroblast subsets suggest that the Tnf-induced ileitis is initiated in the lamina propria via TNF pathway activation in villus-associated fibroblasts (telocytes and PdgfraCd81 cells), which are responsible for the organization of TLOs. Trophocytes drive disease progression in the submucosal layer, accompanied by the excessive formation of granulomas. These findings provide evidence for spatial regulation of inflammation by fibroblast subsets and underscore the pivotal role of fibroblasts in the inception and advancement of ileitis.
克罗恩病（CD）是一种主要影响回肠末端的持续性炎症性疾病。Tnf小鼠由于TNF过度表达而自发发展出类似CD的回肠炎，是人类疾病的可靠模型。在此，通过对Tnf小鼠进行单细胞RNA测序，我们发现小鼠TNF依赖性回肠炎的特征是三级淋巴器官（TLO）中的细胞扩张、T细胞效应器重编程以及黏膜下肉芽肿中活化巨噬细胞的积累。在基质细胞区室中，成纤维细胞亚群（端细胞、滋养细胞、PdgfraCd81细胞）数量较少，而与野生型相比，淋巴管内皮细胞（LEC）和成纤维网状细胞（FRC）显示出相对扩张。所有三个成纤维细胞亚群均表现出强烈的促炎特征。在特定成纤维细胞亚群中进行的TNFR1功能丧失或获得实验表明，Tnf诱导的回肠炎是通过绒毛相关成纤维细胞（端细胞和PdgfraCd81细胞）中的TNF途径激活在固有层中启动的，这些细胞负责TLO的组织。滋养细胞驱动黏膜下层的疾病进展，并伴有肉芽肿的过度形成。这些发现为成纤维细胞亚群对炎症的空间调节提供了证据，并强调了成纤维细胞在回肠炎发生和进展中的关键作用。
