Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

Background: Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjo gren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross- tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases. Methods: We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue- specific phenotypes. Findings: Two shared clusters, CXCL10+CCL19 + immune- interacting and SPARC +COL3A1+ vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro- inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. Conclusions: This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases. Funding: Grant from F. Hoffmann-La Roche (Roche) AG.

Automated summary

This study provides a comprehensive investigation into fibroblasts across different diseases, identifying shared pathogenic activation states and two common types of pro-inflammatory fibroblasts.