1. A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
- Author
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Ng, Michael T. H., Borst, Rowie, Gacaferi, Hamez, Davidson, Sarah, Ackerman, Jessica E., Johnson, Peter A., Machado, Caio C., Reekie, Ian, Attar, Moustafa, Windell, Dylan, Kurowska-Stolarska, Mariola, Macdonald, Lucy, Alivernini, Stefano, Garvilles, Micon, Jansen, Kathrin, Bhalla, Ananya, Lee, Angela, Charlesworth, Jame, Chowdhury, Rajat, Klenerman, Paul, Powell, Kate, Hackstein, Carl-Philip, Rangan, Amar, Gwilym, Stephen, Little, Christopher, Titchener, Andrew, Chaudhury, Salma, Holland, Philip, Wheway, Kim, Watkins, Bridget, Beazley, Debra, Vesty-Edwards, Loi, Appleton, Louise, Atkinson, Marc, Kottam, Lucksy, James, Juliet, Clark, Natalie, Furniss, Dominic, Rees, Jonathan, Gilroy, Derek, Coles, Mark, Carr, Andrew J., Sansom, Stephen N., Buckley, Christopher D., Dakin, Stephanie G., Null, Null, Alivernini, Stefano (ORCID:0000-0002-7383-4212), Ng, Michael T. H., Borst, Rowie, Gacaferi, Hamez, Davidson, Sarah, Ackerman, Jessica E., Johnson, Peter A., Machado, Caio C., Reekie, Ian, Attar, Moustafa, Windell, Dylan, Kurowska-Stolarska, Mariola, Macdonald, Lucy, Alivernini, Stefano, Garvilles, Micon, Jansen, Kathrin, Bhalla, Ananya, Lee, Angela, Charlesworth, Jame, Chowdhury, Rajat, Klenerman, Paul, Powell, Kate, Hackstein, Carl-Philip, Rangan, Amar, Gwilym, Stephen, Little, Christopher, Titchener, Andrew, Chaudhury, Salma, Holland, Philip, Wheway, Kim, Watkins, Bridget, Beazley, Debra, Vesty-Edwards, Loi, Appleton, Louise, Atkinson, Marc, Kottam, Lucksy, James, Juliet, Clark, Natalie, Furniss, Dominic, Rees, Jonathan, Gilroy, Derek, Coles, Mark, Carr, Andrew J., Sansom, Stephen N., Buckley, Christopher D., Dakin, Stephanie G., Null, Null, and Alivernini, Stefano (ORCID:0000-0002-7383-4212)
- Abstract
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.
- Published
- 2024