ABSTRACT Fibrotic conditions are a significant global disease burden. While some therapies delay disease progression, none reverse fibrosis. To gain insights into how fibrosis might resolve, we developed a comparative single cell atlas of frozen shoulder capsule tissue; a chronic inflammatory fibrotic human disease that resolves spontaneously. We identified both a population of pro-inflammatory MERTK low CD48+ macrophages (Mφ) and a population of MERTK+LYVE1+MRC1+Mφ enriched for negative regulators of inflammation. Micro-cultures of patient-derived cells identified cell-matrix interactions between MERTK+Mφ and DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in the resolution of frozen shoulder. Cross-tissue analysis revealed a shared gene expression cassette between MERTK+Mφ in the shoulder capsule and a similar cell population enriched in synovial tissues from rheumatoid arthritis patients in disease remi ssion, supporting the concept that MERTK+Mφ provide a cellular basis for the resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identified MERTK+LYVE1+MRC1+Mφ and DKK3+ and POSTN+ fibroblast populations analogous to those identified in adult shoulder capsule, suggesting that the template to resolve fibrosis is established during development. Therapeutic enhancement of crosstalk between MerTK+Mφ and pro-resolving DKK3+ and POSTN+ fibroblasts could accelerate resolution of frozen shoulder and resolve persistent inflammatory fibrotic disease in other tissues.

Primed to resolve: A single cell atlas of the shoulder capsule reveals a cellular basis for resolving inflammatory fibrosis