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Single-cell and spatial architecture of human tissue granulomas reveals an aberrant immune-regulatory program underlying sarcoidosis [spatial transcriptomics data]

ABSTRACT: Purpose: Granulomas are lumps of immune cells that can form in various organs, causing chronic inflammation and tissue destruction. While most granulomas appear histologically heterogeneous and unstructured, they have a certain resemblance of lymphoid organ formation. We thus pursued the hypothesis that granuloma formation is a highly orchestrated process that mixes and repurposes various regulatory mechanisms of normal development Methods: We performed single-cell sequencing and spatial transcriptomics on granulomas from patients diagnosed with cutaneous sarcoidosis, and we bioinformatically reconstructed their gene-regulatory networks and cell-cell interactions Results: We observed regulatory processes underlying granuloma formation that were highly conserved across individuals and followed characteristic spatial patterns. We identified metabolically reprogrammed macrophages, various T cells subsets and structural cells including fibroblasts and endothelial cells as key players in granulomas. Specifically, exhausted interferon-gamma-producing Th17.1 cells with cytotoxic potential and inflammatory fibroblasts were identified as drivers of granuloma formation by attracting various immune cell types. Summary: we found that granuloma formation in sarcoidosis is a molecular and cellular process that adopts specific aspects of normal lymphoid organ development in aberrant combinations. Our study frames human granuloma formation as a developmental pathology and raises the future perspective of therapeutic targeting of granuloma-specific regulatory programs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192460 | GEO | 2023/02/07

REPOSITORIES: GEO

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Project description:Cardiac involvement is an important determinant of mortality amongst sarcoidosis patients. While granulomatous inflammation is a hallmark finding in cardiac sarcoidosis, the precise immune cell populations that comprise the granuloma remain unresolved. Furthermore, it is unclear how the cellular and transcriptomic landscape of cardiac sarcoidosis differs from other inflammatory heart diseases. We leveraged spatial transcriptomics (GeoMx DSP) and single nucleus RNA sequencing (snRNAseq) to elucidate the cellular and transcriptional landscape of cardiac sarcoidosis. Using GeoMX DSP technology, we compared the transcriptomal profile of CD68+ rich immune cell infiltrates in human cardiac sarcoidosis, giant cell myocarditis, and lymphocytic myocarditis. We performed snRNAseq of human cardiac sarcoidosis to identify immune cell types and examined their transcriptomic landscape and regulation. Using multi-channel immunofluorescence staining, we validated immune cell populations identified by snRNAseq, determined their spatial relationship, and devised an immunostaining approach to distinguish cardiac sarcoidosis from other inflammatory heart diseases. Despite overlapping histological features, spatial transcriptomics identified transcriptional signatures and associated pathways that robustly differentiated cardiac sarcoidosis from giant cell myocarditis and lymphocytic myocarditis. snRNAseq revealed the presence of diverse populations of myeloid cells in cardiac sarcoidosis with distinct molecular features. We identified GPNMB as a novel marker of multinucleated giant cells and predicted that the MITF family of transcription factors regulated this cell type. We also detected additional macrophage populations in cardiac sarcoidosis including HLA-DR+ macrophages, SYTL3+ macrophages and CD163+ resident macrophages. HLA-DR+ macrophages were found immediately adjacent to GPMMB+ giant cells, a distinct feature compared with other inflammatory cardiac diseases. SYTL3+ macrophages were located scattered throughout the granuloma and CD163+ macrophages, CD1c+ dendritic cells, non-classical monocytes, and T-cells were located at the periphery and outside of the granuloma. Finally, we demonstrate mTOR pathway activation is associated with proliferation and is selectively found in HLA-DR+ and SYLT3+ macrophages. In this study, we identified diverse populations of immune cells with distinct molecular signatures that comprise the sarcoid granuloma. These findings provide new insights into the pathology of cardiac sarcoidosis and highlight opportunities to improve diagnostic testing.

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Single-cell and spatial architecture of human tissue granulomas reveals an aberrant immune-regulatory program underlying sarcoidosis [spatial transcriptomics data]

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