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Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

Authors :
Adam P. Croft
Loriane Savary
Ilya Lorsunsky
Jennifer L. Marshall
Andrew Filer
Helen M. McGettrick
Mark Coles
Christopher D. Buckley
Moustafa Attar
Francesca Barone
Stephen N. Sansom
Kevin Wei
Soumya Raychaudhuri
Harris Perlman
Joana Campos
Kathrin Jansen
Jason D. Turner
Michael B. Brenner
Douglas T. Fearon
Publication Year :
2018
Publisher :
Cold Spring Harbor Laboratory, 2018.

Abstract

SUMMARYThe identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune mediated inflammatory diseases (IMIDs). 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 damage. 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 FAPα+ synovial cells suppressed both inflammation and bone erosions in murine models of resolving and persistent arthritis. Single cell transcriptional analysis identified two distinct fibroblast subsets: FAPα+ THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAPα+ THY1- destructive fibroblasts restricted to the synovial lining. When adoptively transferred into the joint, FAP α+ THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation whereas transfer of FAP α+ 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....d45e77d48eeaab9f41152e11a7ebbba5
Full Text :
https://doi.org/10.1101/374330