Publications Search

Search for publications by author
Search for publications by abstract keyword(s)

Spontaneously Resolving Joint Inflammation Is Characterised by Metabolic Agility of Fibroblast-Like Synoviocytes


Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and orchestrating local inflammatory processes. When activated during injury or inflammation, FLS undergo transiently increased bioenergetic and biosynthetic demand. We aimed to identify metabolic changes which occur early in inflammatory disease pathogenesis which might support sustained cellular activation in persistent inflammation. We took primary human FLS from synovial biopsies of patients with very early rheumatoid arthritis (veRA) or resolving synovitis, and compared them with uninflamed control samples from the synovium of people without arthritis. Metabotypes were compared using NMR spectroscopy-based metabolomics and correlated with serum C-reactive protein levels. We measured glycolysis and oxidative phosphorylation by Seahorse analysis and assessed mitochondrial morphology by immunofluorescence. We demonstrate differences in FLS metabolism measurable after ex vivo culture, suggesting that disease-associated metabolic changes are long-lasting. We term this phenomenon 'metabolic memory'. We identify changes in cell metabolism after acute TNFalpha stimulation across disease groups. When compared to FLS from patients with early rheumatoid arthritis, FLS from patients with resolving synovitis have significantly elevated mitochondrial respiratory capacity in the resting state, and less fragmented mitochondrial morphology after TNFalpha treatment. Our findings indicate the potential to restore cell metabotypes by modulating mitochondrial function at sites of inflammation, with implications for treatment of RA and related inflammatory conditions in which fibroblasts play a role.

Type Journal
ISBN 1664-3224 (Electronic) 1664-3224 (Linking)
Authors Falconer, J.; Pucino, V.; Clayton, S. A.; Marshall, J. L.; Raizada, S.; Adams, H.; Philp, A.; Clark, A. R.; Filer, A.; Raza, K.; Young, S. P.; Buckley, C. D.
Responsible Garvan Author Dr Andy Philp
Publisher Name Frontiers in Immunology
Published Date 2021-08-31
Published Volume 12
Published Pages 725641
Status Published in-print
DOI 10.3389/fimmu.2021.725641
URL link to publisher's version