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January 05, 2026 article Open access Aachen paper

Spatial transcriptomics uncovers hybrid, proinflammatory, and profibrotic cellular niches in pulmonary granuloma of patients with chronic sarcoidosis

American Journal of Respiratory and Critical Care Medicine, vol. 212, pp. 338–350

DOI: 10.1093/ajrccm/aamaf089 Full text (OA) OpenAlex

Abstract

BACKGROUND: Sarcoidosis is a disease of unknown etiology, characterized by the formation of immune cell accumulations (granulomas) in the lung and other tissues. Chronic sarcoidosis may lead to pulmonary fibrosis. AIM: To unravel cellular niches within pulmonary granulomas of patients with chronic sarcoidosis using spatial transcriptomics. METHODS: Spatial transcriptomics using the Visium platform (10x Genomics) was performed on 9 granuloma-containing lung explants from patients with sarcoidosis. Validation of gene expression was performed through immunohistofluorescence protein staining and RNA in situ hybridization. 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-cell and CD20+ B-cell niche in close proximity, surrounded by a COL3A1+ fibroblast niche. In the Central Granuloma Macrophage niche, expression of the profibrotic macrophage genes SPP1, CHIT1, and CHI3L1 was observed, genes whose expression has recently been described for macrophages in idiopathic pulmonary fibrosis. Additionally, proinflammatory macrophage genes were expressed in the Central Granuloma Macrophage niche, suggesting that macrophages were armed for lysosomal degradation and ready for phagocytosis. Inner granuloma niches showed higher expression of interferon gamma (IFN-γ)-inducible genes. Higher collagen and CTHRC1 expression were observed in fibroblast-containing granuloma niches, characteristics of profibrotic lung remodeling. Ligand-receptor analysis identified proinflammatory and profibrotic interactions between granuloma niches. CONCLUSION: Taken together, macrophages in the center of the sarcoidosis granuloma form an armed-and-ready, hybrid proinflammatory and profibrotic niche, supporting granuloma persistence through continuous IFN-γ stimulation and collagen expression by fibroblasts localized in the periphery of the granuloma.

Authors 25

  1. Leonard Christian

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  2. Hande Yilmaz

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  3. Jannik Ruwisch

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  4. Leon Giercke

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  5. Benjamin Seeliger

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  6. Jan C. Kamp

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  7. Sirvan Bayraktar

    Medizinische Hochschule Hannover

    Affiliation as printed

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  8. Raphael Ewen

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  9. Theresa Graalmann

    Medizinische Hochschule Hannover · German Center for Lung Research · Center for Experimental and Clinical Infection Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department for Rheumatology and Immunology, Hannover Medical School (MHH) , Hannover,

    Junior Research Group Translational Immunology, TWINCORE, Center for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Center for Infection Research (HZI) and the Hannover Medical School (MHH) , Hannover,

  10. Jan Fuge

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  11. Mark Greer

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  12. Fabio Ius

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Clinic for Cardiac, Thoracic, Transplant and Vascular Surgery, Hannover Medical School (MHH) , Hannover,

  13. Tobias Welte

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  14. Shu-Yi Liao

    National Jewish Health

    Affiliation as printed

    Department of Medicine, National Jewish Health , Denver, CO,

  15. Ivana V. Yang

    Colorado School of Public Health · University of Colorado Anschutz

    Affiliation as printed

    Department of Epidemiology, Colorado School of Public Health , Aurora, CO,

    Department of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO,

  16. Jens Michael Hohlfeld

    Medizinische Hochschule Hannover · Fraunhofer Institute for Toxicology and Experimental Medicine · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

    Division of Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) , Hannover,

  17. Marius M. Hoeper

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  18. Jens Gottlieb

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

  19. Naftali Kaminski

    Yale University

    Affiliation as printed

    Pulmonary, Critical Care and Sleep Medicine, Yale University , New Haven, CT,

  20. Antje Prasse

    University of Basel · University Hospital of Basel · Medizinische Hochschule Hannover · Fraunhofer Institute for Toxicology and Experimental Medicine · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Clinics of Respiratory Medicine, University Hospital Basel, University of Basel , Basel,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

    Division of Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) , Hannover,

  21. Danny David Jonigk Aachen

    Medizinische Hochschule Hannover · Universitätsklinikum Aachen · German Center for Lung Research · RWTH Aachen University

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Institute of Pathology, Hannover Medical School (MHH) , Hannover,

    University Clinic of the RWTH Aachen , Aachen,

  22. Yang Li

    Radboud University Nijmegen · Radboud University Medical Center · Medizinische Hochschule Hannover · Centre for Individualised Infection Medicine · Center for Experimental and Clinical Infection Research · CAIMed - Niedersächsisches Zentrum für KI und Kausale Methoden in der Medizin

    Affiliation as printed

    Cluster of Excellence Resolving Infection Susceptibility (RESIST) , Hannover,

    Computational Biology for Individualised Medicine, TWINCORE, Center for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Center for Infection Research (HZI) and the Hannover Medical School (MHH) , Hannover,

    Department of Computational Biology for Individualised Medicine, Center for Individualised Infection Medicine (CiiM), a Joint Venture between the Helmholtz Center for Infection Research (HZI) and the Hannover Medical School (MHH) , Hannover,

    Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen,

    Lower Saxony Center for Artificial Intelligence and Causal Methods in Medicine (CAIMed) , Hannover,

  23. Christine Susanne Falk

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Institute of Transplant Immunology, Hannover Medical School (MHH) , Hannover,

  24. Lavinia Neubert

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Institute of Pathology, Hannover Medical School (MHH) , Hannover,

  25. Jonas C. Schupp corresponding

    Yale University · Medizinische Hochschule Hannover · Fraunhofer Institute for Toxicology and Experimental Medicine · German Center for Lung Research

    Affiliation as printed

    Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL) , Hannover,

    Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School (MHH) , Hannover,

    Division of Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) , Hannover,

    Pulmonary, Critical Care and Sleep Medicine, Yale University , New Haven, CT,

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References 54