Croft, A. P., Campos, J., Jansen, K., Turner, J. D., Marshall, J., Attar, M., Savary, L., Wehmeyer, C., Naylor, A. J., Kemble, S., Begum, J., Durholz, K., Perlman, H., Barone, F., McGettrick, H. M., Fearon, D. T., Wei, K., Raychaudhuri, S., Korsunsky, I., Brenner, M. B., Coles, M., Sansom, S. N., Filer, A., Buckley, C. D. (May 2019) Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature, 570 (7760). pp. 246-251. ISSN 0028-0836
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 damage(3-5). 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-alpha (FAPalpha)(+) 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 FAPalpha(+) population: FAPalpha(+)THY1(+) immune effector fibroblasts located in the synovial sub-lining, and FAPalpha(+)THY1(-) destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPalpha(+)THY1(-) fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPalpha(+) 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.
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