Research from Lida Iliopoulou et al. at the Kollias lab uncovers how distinct fibroblast subtypes spatially regulate intestinal inflammation via TNFR1 signaling.
Crohn’s disease (CD) is marked by deep, penetrating inflammation across the intestinal wall, yet the mechanisms underlying its spatial restriction remain poorly understood. In a new study published in Nature Communications, the authors use high-resolution single-cell analysis in the TnfΔARE murine model of CD-ileitis to reveal region-specific immune cell niche expansion: tertiary lymphoid organs (TLOs), predominantly composed of B cells, form in the lamina propria, and granulomas, segregation of an activated subset of macrophages in the submucosa. In parallel, intestinal fibroblasts dynamically shift their roles, acquiring highly pro-inflammatory properties such as chemoattraction—directly driven by TNFR1 signaling.
Most notably, the study shows that the initiation and progression of inflammation rely on TNFR1 activation in two distinct fibroblast populations. Villous-associated fibroblasts, including telocytes and PdgfraloCd81- cells, are essential for TLO formation in the lamina propria, while crypt-associated fibroblasts, known as trophocytes, drive the deeper spread of inflammation into the intestinal wall, and the expansion of granulomas in this area.
This work highlights how fibroblast heterogeneity shapes the spatial dynamics of inflammation in CD and suggests that fibroblast-targeted modulation of TNF responses offers a promising strategy to decouple mucosal from submucosal inflammation and prevent its progression into chronic disease.
Publication: Iliopoulou, L., Tzaferis, C., Prados, A. et al. Different fibroblast subtypes propel spatially defined ileal inflammation through TNFR1 signalling in murine ileitis. Nat Commun 16, 3023 (2025). https://doi.org/10.1038/s41467-025-57570-7