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 unstruc-tured, 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 sarcoid-osis 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, cyto-kine-producing Th17.1 cells, and fibroblasts with inflammatory and tissue-remodeling phenotypes. Pharma-cological 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 develop-ment in aberrant combinations, indicating that granulomas constitute aberrant lymphoid organs.

Automated summary

By analyzing granulomas from sarcoidosis patients, researchers reconstructed the gene regulatory networks involved in granuloma formation. They found that granulomas adopt aspects of lymphoid organ development and involve processes related to immunometabolism, cytokine and chemokine signaling, and extracellular matrix remodeling. Three cell types, including metabolically reprogrammed macrophages, cytokine-producing Th17.1 cells, and fibroblasts with inflammatory and tissue-remodeling phenotypes, were identified as key players in granuloma formation. Inhibiting one of the identified processes attenuated granuloma formation in a mouse model of sarcoidosis.