A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution

Michael T. H. Ng (), Rowie Borst, Hamez Gacaferi, Sarah Davidson, Jessica E. Ackerman, Peter A. Johnson, Caio C. Machado, Ian Reekie, Moustafa Attar, Dylan Windell, Mariola Kurowska-Stolarska, Lucy MacDonald, Stefano Alivernini, Micon Garvilles, Kathrin Jansen, Ananya Bhalla, Angela Lee, James Charlesworth, Rajat Chowdhury, Paul Klenerman, Kate Powell, Carl-Philip Hackstein, Dominic Furniss, Jonathan Rees, Derek Gilroy, Mark Coles, Andrew J. Carr, Stephen N. Sansom, Christopher D. Buckley and Stephanie G. Dakin ()
Additional contact information
Michael T. H. Ng: University of Oxford
Rowie Borst: University of Oxford
Hamez Gacaferi: University of Oxford
Sarah Davidson: University of Oxford
Jessica E. Ackerman: University of Oxford
Peter A. Johnson: University of Oxford
Caio C. Machado: University of Oxford
Ian Reekie: University of Oxford
Moustafa Attar: University of Oxford
Dylan Windell: University of Oxford
Mariola Kurowska-Stolarska: University of Glasgow
Lucy MacDonald: University of Glasgow
Stefano Alivernini: Fondazione Policlinico Universitario Agostino Gemelli – IRCCS
Micon Garvilles: University of Oxford
Kathrin Jansen: University of Oxford
Ananya Bhalla: University of Oxford
Angela Lee: University of Oxford
James Charlesworth: University of Oxford
Rajat Chowdhury: University of Oxford
Paul Klenerman: University of Oxford
Kate Powell: University of Oxford
Carl-Philip Hackstein: University of Oxford
Dominic Furniss: University of Oxford
Jonathan Rees: University of Oxford
Derek Gilroy: University College London
Mark Coles: University of Oxford
Andrew J. Carr: University of Oxford
Stephen N. Sansom: University of Oxford
Christopher D. Buckley: University of Oxford
Stephanie G. Dakin: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45341-9

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