Single-cell and spatial transcriptomics reveal aberrant lymphoid developmental programs driving granuloma formation.

Granulomas are lumps of immune cells that can form in various organs. Most granulomas appear unstructured, yet they have some resemblance to lymphoid organs. To better understand granuloma formation, we performed single-cell sequencing and spatial transcriptomics on granulomas from patients with sarcoidosis and bioinformatically reconstructed the underlying gene regulatory networks. We discovered an immune stimulatory environment in granulomas that repurposes transcriptional programs associated with lymphoid organ development. Granuloma formation followed characteristic spatial patterns and involved genes linked to immunometabolism, cytokine and chemokine signaling, and extracellular matrix remodeling. Three cell types emerged as key players in granuloma formation: metabolically reprogrammed macrophages, cytokine-producing Th17.1 cells, and fibroblasts with inflammatory and tissue-remodeling phenotypes. Pharmacological inhibition of one of the identified processes attenuated granuloma formation in a sarcoidosis mouse model. We show that human granulomas adopt characteristic aspects of normal lymphoid organ development in aberrant combinations, indicating that granulomas constitute aberrant lymphoid organs. [Display omitted] • Performed single-cell sequencing and spatial transcriptomics on sarcoidosis granulomas • Reconstructed the architecture of granulomas and their gene regulatory networks • Identified a network of pathogenic macrophages, T cells, and fibroblasts in granulomas • Tested mechanisms shared with lymphoid organ development as drug targets in sarcoidosis Granulomas are accumulations of immune cells that help contain infections but can also give rise to diseases. To better understand granuloma formation, Krausgruber et al. perform single-cell and spatial profiling of sarcoidosis-associated skin granulomas. They find that granulomas exploit molecular mechanisms underlying the formation of tertiary lymphoid structures but lack their overall control, indicating that granulomas constitute aberrant lymphoid organs. [ABSTRACT FROM AUTHOR]