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

Ng, M. T.; Borst, R.; Gacaferi, H.; Davidson, S.; Machado, C. C.; 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 Study group,; Furniss, D.; Rees, J.; Gilroy, D.; Coles, M.; Carr, A. J.; Sansom, S. N.; Buckley, C. D.; Dakin, S. G.

doi:10.1101/2023.01.16.522218

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bioRxiv · 10.1101/2023.01.16.522218

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

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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 MERTKlowCD48+ macrophages (M{varphi}) and a population of MERTK+LYVE1+MRC1+M{varphi} enriched for negative regulators of inflammation. Micro-cultures of patient-derived cells identified cell-matrix interactions between MERTK+M{varphi} 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+M{varphi} 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+M{varphi} 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+M{varphi} 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+M{varphi} and pro-resolving DKK3+ and POSTN+ fibroblasts could accelerate resolution of frozen shoulder and resolve persistent inflammatory fibrotic disease in other tissues.

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Ng, M. T., Borst, R., Gacaferi, H., Davidson, S., Machado, C. C., 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 Study group,, Furniss, D., Rees, J., Gilroy, D., Coles, M., Carr, A. J., Sansom, S. N., Buckley, C. D., Dakin, S. G.. 2023-01-16. Primed to resolve: A single cell atlas of the shoulder capsule reveals a cellular basis for resolving inflammatory fibrosis. https://doi.org/10.1101/2023.01.16.522218

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