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

Falconer, Jane, Pucino, Valentina, Clayton, Sally A., Marshall, Jennifer L., Raizada, Sabrina, Adams, Holly, Philp, Andrew, Clark, Andrew R., Filer, Andrew, Raza, Karim, Young, Stephen P. and Buckley, Christopher D. (2021) Spontaneously Resolving Joint Inflammation Is Characterised by Metabolic Agility of Fibroblast-Like Synoviocytes. Frontiers in Immunology, 12. p. 725641. ISSN 1664-3224

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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 TNFα 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 TNFα 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.

Item Type: Article
Additional Information: ** From Frontiers via Jisc Publications Router ** History: collection 2021; received 15-06-2021; accepted 09-08-2021; epub 26-08-2021. ** Licence for this article: http://creativecommons.org/licenses/by/4.0/
Uncontrolled Keywords: Immunology, fibroblasts, arthritis, inflammation, metabolism, mitochondria
Divisions: Faculty of Health Sciences and Wellbeing > School of Medicine
Related URLs:
SWORD Depositor: Publication Router
Depositing User: Publication Router
Date Deposited: 13 Sep 2021 19:31
Last Modified: 13 Sep 2021 19:31
URI: http://sure.sunderland.ac.uk/id/eprint/13947
ORCID for Jane Falconer: ORCID iD orcid.org/0000-0002-6601-7919

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