Distinct fibroblast subsets drive inflammation and damage in arthritis.

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.

• Authors: 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, Christopher D Buckley
• Journal: Nature (Nature) Vol. 570 Issue 7760 Pg. 246-251 (06 2019) ISSN: 1476-4687 [Electronic] England
• PMID: 31142839 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• Thy-1 Antigens
• Endopeptidases
• Serine Endopeptidases
• fibroblast activation protein alpha
• Gelatinases

Topics

• Animals
• Arthritis, Rheumatoid (pathology)
• Bone and Bones (pathology)
• Endopeptidases
• Female
• Fibroblasts (classification, metabolism, pathology)
• Gelatinases (metabolism)
• Humans
• Inflammation (pathology)
• Joints (pathology)
• Male
• Membrane Proteins (metabolism)
• Mice
• RNA-Seq
• Serine Endopeptidases (metabolism)
• Single-Cell Analysis
• Synovial Membrane (pathology)
• Thy-1 Antigens (metabolism)