Spatial transcriptomics uncovers hybrid, pro-inflammatory and pro-fibrotic cellular niches in pulmonary granuloma of patients with chronic sarcoidosis

  1. Leonard Christian
  2. Hande Yilmaz
  3. Jannik Ruwisch
  4. Leon Giercke
  5. Benjamin Seeliger
  6. Jan C. Kamp
  7. Sirvan Bayraktar
  8. Raphael Ewen
  9. Theresa Graalmann
  10. Jan Fuge
  11. Mark Greer
  12. Fabio Ius
  13. Tobias Welte
  14. Jens M. Hohlfeld
  15. Marius M. Hoeper
  16. Jens Gottlieb
  17. Naftali Kaminski
  18. Antje Prasse
  19. Danny Jonigk
  20. Yang Li
  21. Christine Falk
  22. Lavinia Neubert
  23. Jonas C. Schupp
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Abstract

Background

Sarcoidosis is a disease of unknown etiology characterized by the formation of immune cell accumulation (granuloma) in the lung and other tissues. Chronic sarcoidosis may lead to pulmonary fibrosis.

Aim

To unravel cellular niches within pulmonary granuloma of chronic sarcoidosis patients using spatial transcriptomics.

Methods

Spatial transcriptomics using the Visium platform (10x Genomics) was performed on nine granuloma-containing lung explants from sarcoidosis patients. Validation of gene expression was performed through immunohistofluorescence protein staining and RNAin situhybridization.

Results

Spatial gene expression covered 30,587 gene expression spots and 173 granulomas. A CD68+macrophage niche was localized in the center of the granuloma, with a CD3+T and CD20+B cell niche in close proximity, surrounded by a COL3A1+fibroblast niche. In the central granuloma macrophage niche, expression of the pro-fibrotic macrophage genesSPP1,CHIT1andCHI3L1was observed, genes whose expression has recently been described for macrophages in idiopathic pulmonary fibrosis. Additionally, pro-inflammatory macrophage genes were expressed in the central granuloma niche: macrophages appear armed for lysosomal degradation and ready for phagocytosis. Inner granuloma niches showed high responsiveness to interferon gamma (IFN-γ), expressing a multitude of IFN-γ-induced genes. High collagen andCTHRC1expression were observed in granuloma fibroblasts niches, characteristics of pro-fibrotic lung remodeling. Ligand-receptor analysis identified pro-inflammatory and pro-fibrotic interactions between granuloma niches.

Conclusion

Taken together, macrophages in the center of the sarcoidosis granuloma form an armed-and-ready, hybrid pro-inflammatory and pro-fibrotic niche, supporting granuloma persistence through continuous IFN-γ-stimulation and fibrotic remodeling conducted by fibrotic fibroblasts surrounding the granuloma.

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