Sarcoidosis is a systemic granulomatous disease of unknown cause that predominantly affects the lungs and, in some patients, progresses to pulmonary fibrosis. The granulomatous lesion itself is a characteristic histological structure in which immune cells, B and T lymphocytes, and fibroblastic cells are densely organized. However, the cellular programs and interactions underlying this dysregulation have remained unclear.

Methodological approach: spatial resolution of granulomatous cell niches

In this study, the researchers applied spatial transcriptomics—a technique that combines gene expression data with spatial information to characterize cellular niches in situ. More than 30,000 expression spots from granulomatous lung tissue samples were analyzed, enabling detailed mapping of gene expression patterns within and surrounding the granulomas.

The key discovery: the macrophage niche at the center of the granulomas exhibits a hybrid activation pattern that simultaneously activates both pro-inflammatory and pro-fibrotic programs. This dual gene expression signature includes genes associated with lysosomal activation, phagocytosis, and the promotion of connective tissue formation—challenging the traditional dichotomy between inflammation and fibrosis in immunological research.

Surrounding these central macrophages were T and B cells, while fibrotic niche zones were characterized by increased expression of collagen and matrix-remodeling genes. Ligand–receptor analyses indicated intense intercellular communication between the niches, suggesting specific mechanistic links between inflammation and fibrotic remodeling.

Relevance for translational lung research

These findings are of particular importance for translational lung research, as the study demonstrates for the first time at spatial resolution how inflammatory and fibrotic tissue remodeling processes are functionally interconnected within a single granulomatous lung lesion. Using spatial transcriptomics, the researchers showed that macrophages in the center of chronic sarcoidosis granulomas simultaneously activate pro-inflammatory and pro-fibrotic programs, adopting a hybrid cellular identity not previously described in this form.

These cells are embedded in a complex network of adaptive immune cells and fibrosis-associated stromal cells, whose close spatial interaction appears to be crucial for disease chronicity.

“Our data show that granulomatous inflammation and fibrosis must not be understood as separate processes. If we want to develop targeted therapies in the future, we need to address these locally organized cellular networks as a functional unit—not individual cell types in isolation,” agree the two first authors and BREATH early-career researchers Leonard Christian and Hande Yilmaz.

The study thus provides a mechanistic foundation for new translational approaches that directly target the disease-defining microstructures of the lung.

Original publication:

Leonard Christian*, Hande Yilmaz*, Jannik Ruwisch, Leon Giercke, Benjamin Seeliger, Jan C. Kamp, Sirvan Bayraktar, Raphael Ewen, Theresa Graalmann, Jan Fuge, Mark Greer, Fabio Ius, Tobias Welte, Shu-Yi Liao, Ivana V. Yang, Jens M. Hohlfeld, Marius M. Hoeper, Jens Gottlieb, Naftali Kaminski, Antje Prasse, Danny Jonigk, Yang Li, Christine Falk, Lavinia Neubert*, Jonas C. Schupp*, Spatial Transcriptomics Uncovers Hybrid, Pro-Inflammatory and Pro-Fibrotic Cellular Niches in Pulmonary Granuloma of Patients with Chronic Sarcoidosis, American Journal of Respiratory and Critical Care Medicine, 2026; aamaf089.

* contributed equally

Text: BREATH/AB

Photo: BREATH/ AB

Text: BREATH/AB

Foto: BREATH/AB