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

Korsunsky, Ilya; Wei, Kevin; Pohin, Mathilde; Kim, Edy Y.; Barone, Francesca; Kang, Joyce B.; Friedrich, Matthias; Turner, Jason; Nayar, Saba; Fisher, Benjamin A.; Raza, Karim; Marshall, Jennifer L.; Croft, Adam P.; Sholl, Lynette M.; Vivero, Marina; Rosas, Ivan O.; Bowman, Simon J.; Coles, Mark; Frei, Andreas P.; Lassen, Kara; Filer, Andrew; Powrie, Fiona; Buckley, Christopher D.; Brenner, Michael B.; Raychaudhuri, Soumya

Pro-inflammatory fibroblasts are critical to pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren’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 the understanding of which pathways are shared by multiple diseases. To investigate, we profiled patient-derived fibroblasts from inflamed and non-inflamed synovium, intestine, lung, and salivary glands with single-cell RNA-sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. Two shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts were expanded in all inflamed tissues and additionally mapped to dermal analogues in a public atopic dermatitis atlas. We further confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. This work represents the first cross-tissue, single-cell fibroblast atlas revealing shared pathogenic activation states across four chronic inflammatory diseases.