Distinct fibroblast subsets drive inflammation and damage in arthritis

Adam P. Croft, Joana Campos, Kathrin Jansen, Jason D. Turner, Jennifer Marshall, Moustafa Attar, Loriane Savary, Corinna Wehmeyer, Amy J. Naylor, Samuel Kemble, Jenefa Begum, Kerstin Dürholz, Harris Perlman, Francesca Barone, Helen M. McGettrick, Douglas T. Fearon, Kevin Wei, Soumya Raychaudhuri, Ilya Korsunsky, Michael B. Brenner, Mark Coles, Stephen N. Sansom, Andrew Filer and Christopher D. Buckley ()
Additional contact information
Adam P. Croft: University of Birmingham, Queen Elizabeth Hospital
Joana Campos: University of Birmingham, Queen Elizabeth Hospital
Kathrin Jansen: University of Oxford
Jason D. Turner: University of Birmingham, Queen Elizabeth Hospital
Jennifer Marshall: University of Birmingham, Queen Elizabeth Hospital
Moustafa Attar: University of Oxford
Loriane Savary: University of Birmingham, Queen Elizabeth Hospital
Corinna Wehmeyer: University of Birmingham, Queen Elizabeth Hospital
Amy J. Naylor: University of Birmingham, Queen Elizabeth Hospital
Samuel Kemble: University of Birmingham, Queen Elizabeth Hospital
Jenefa Begum: University of Birmingham, Queen Elizabeth Hospital
Kerstin Dürholz: University of Birmingham, Queen Elizabeth Hospital
Harris Perlman: Northwestern University, Feinberg School of Medicine Chicago
Francesca Barone: University of Birmingham, Queen Elizabeth Hospital
Helen M. McGettrick: University of Birmingham, Queen Elizabeth Hospital
Douglas T. Fearon: Cold Spring Harbor Laboratory
Kevin Wei: Brigham and Women’s Hospital, Harvard Medical School
Soumya Raychaudhuri: Brigham and Women’s Hospital, Harvard Medical School
Ilya Korsunsky: Brigham and Women’s Hospital, Harvard Medical School
Michael B. Brenner: Brigham and Women’s Hospital, Harvard Medical School
Mark Coles: University of Oxford
Stephen N. Sansom: University of Oxford
Andrew Filer: University of Birmingham, Queen Elizabeth Hospital
Christopher D. Buckley: University of Birmingham, Queen Elizabeth Hospital

Nature, 2019, vol. 570, issue 7760, 246-251

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1263-7

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