Abstract
Activation of endothelium and immune cells is fundamental to the initiation of autoimmune diseases such as rheumatoid arthritis (RA), and it results in trans-endothelial cell migration and synovial fibroblast proliferation, leading to joint destruction. In RA, the synovial microvasculature is highly dysregulated, resulting in inefficient oxygen perfusion to the synovium, which, along with the high metabolic demands of activated immune and stromal cells, leads to a profoundly hypoxic microenvironment. In inflamed joints, infiltrating immune cells and synovial resident cells have great requirements for energy and nutrients, and they adapt their metabolic profiles to generate sufficient energy to support their highly activated inflammatory states. This shift in metabolic capacity of synovial cells enables them to produce the essential building blocks to support their proliferation, activation and invasiveness. Furthermore, it results in the accumulation of metabolic intermediates and alteration of redox-sensitive pathways, affecting signalling pathways that further potentiate the inflammatory response. Importantly, the inflamed synovium is a multicellular tissue, with cells differing in their metabolic requirements depending on complex cell–cell interactions, nutrient supply, metabolic intermediates and transcriptional regulation. Therefore, understanding the complex interplay between metabolic and inflammatory pathways in synovial cells in RA will provide insight into the underlying mechanisms of disease pathogenesis.
Key points
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Neoangiogenesis and synovial expansion induce a bioenergetic crisis in the inflamed joint in rheumatoid arthritis (RA).
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In RA compared with healthy tissue, synovial fibroblasts undergo a metabolic shift associated with increased invasive capacity and disease activity.
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In RA, synovial stromal–immune cell interactions lead to reciprocal metabolic changes that potentiate the inflammatory response.
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In RA, myeloid cells display metabolic abnormalities associated with increased inflammatory function.
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In RA, T cell polarization and cytokine production are linked to metabolic reprogramming, and B cells are resistant to hypoxia-induced inhibition of pro-inflammatory cytokine secretion.
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Metabolic reprogramming could represent a new therapeutic strategy for patients with RA.
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Fearon, U., Hanlon, M.M., Floudas, A. et al. Cellular metabolic adaptations in rheumatoid arthritis and their therapeutic implications. Nat Rev Rheumatol 18, 398–414 (2022). https://doi.org/10.1038/s41584-022-00771-x
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DOI: https://doi.org/10.1038/s41584-022-00771-x
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