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Nature. 2019 Jun;570(7760):246-251. doi: 10.1038/s41586-019-1263-7. Epub 2019 May 29.

Distinct fibroblast subsets drive inflammation and damage in arthritis.

Author information

1
Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
2
Versus Arthritis Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
3
The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
4
Musculoskeletal Medicine, University of Muenster, Muenster, Germany.
5
Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
6
Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine Chicago, Evanston, IL, USA.
7
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
8
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
9
University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
10
MRC and Versus Arthritis Centre for Musculoskeletal Ageing Research (CMAR), College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
11
Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK. c.d.buckley@bham.ac.uk.
12
Versus Arthritis Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK. c.d.buckley@bham.ac.uk.
13
The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. c.d.buckley@bham.ac.uk.
14
MRC and Versus Arthritis Centre for Musculoskeletal Ageing Research (CMAR), College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK. c.d.buckley@bham.ac.uk.

Abstract

The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)1,2. However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage3-5. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα)+ fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα+ population: FAPα+THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAPα+THY1- destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα+THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα+ THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage.

PMID:
31142839
PMCID:
PMC6690841
[Available on 2019-11-29]
DOI:
10.1038/s41586-019-1263-7

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