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

Ng, M. T.H. et al. (2024) A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution. Nature Communications, 15, 1394. (doi: 10.1038/s41467-024-45341-9) (PMID:38374174) (PMCID:PMC10876649)

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.

• Item Type: Articles
• Additional Information: The human foetal material was provided by the Joint MRC/Wellcome Trust (grant# MR/R006237/1) Human Developmental Biology Resource (http://hdbr.org). We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of sequencing data. Cell DIVE equipment in the Digital Pathology Omics Core was generously funded by the Kennedy Trust for Rheumatology Research. Research at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford is supported through the National Institute for Health Research Oxford Musculoskeletal Biomedical Research Centre. We acknowledge the following funding sources: Versus Arthritis Career Development Fellowship (22425), Medical Research Council MR/S035850/1 Human Immune Discovery Initiative (0006565 and 0008181) & the NIHR Biomedical Research Centre, Oxford, Dunhill Medical Trust RTF1906\121, Rosetrees Trust (PGL21/10048), Wellcome Trust (222426/Z/21/Z), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES)
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kurowska-Stolarska, Professor Mariola and MacDonald, Dr Lucy
• Authors: Ng, M. T.H., Borst, R., Gacaferi, H., Davidson, S., Ackerman, J. E., Johnson, P. A., 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., Furniss, D., Rees, J., Gilroy, D., Coles, M., Carr, A. J., Sansom, S. N., Buckley, C. D., and Dakin, S. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2024 The Authors
• First Published: First published in Nature Communications 15:1394
• Publisher Policy: Reproduced under a Creative Commons License