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

Frontiers in Immunology

Karim Raza¹  Sally A. Clayton³  Christopher D. Buckley⁴  Jennifer L. Marshall⁵  Valentina Pucino⁵  Andrew R. Clark⁵  Sabrina Raizada⁵  Holly Adams⁵  Andrew Filer⁵  Stephen P. Young⁵  Jane Falconer⁶  Andrew Philp⁷ 

[1] Department of Rheumatology, Sandwell and West Birmingham NHS Trust, Birmingham, United Kingdom;Healthy Ageing Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia;Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom;Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom;Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom;School of Medicine, Institute of Health Sciences and Wellbeing, University of Sunderland, Sunderland, United Kingdom;St Vincent’s Clinical School, UNSW Medicine, UNSW Sydney, Sydney, NSW, Australia;

关键词: fibroblasts;    arthritis;    inflammation;    metabolism;    mitochondria;   

DOI  :  10.3389/fimmu.2021.725641

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown