A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution.
Ng MTH., Borst R., Gacaferi H., Davidson S., Ackerman JE., Johnson PA., Machado CC., Reekie I., Attar M., Windell D., Kurowska-Stolarska M., MacDonald L., Alivernini S., Garvilles M., Jansen K., Bhalla A., Lee A., Charlesworth J., Chowdhury R., Klenerman P., Powell K., Hackstein C-P., ICECAP Consortium None., Furniss D., Rees J., Gilroy D., Coles M., Carr AJ., Sansom SN., Buckley CD., Dakin SG.
Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.