Cell metabolism has long been at the forefront of tumour biology, but in the past decade the importance of cellular bioenergetics has been increasingly recognized in regulating immune cell function. Mechanistic studies in 2018 have highlighted cell metabolism as a potential therapeutic target for the treatment of rheumatoid arthritis.
Key advances
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Fibroblast-like synoviocytes are hyper-glycolytic and express large amounts of hexokinase 2 (HK2), which mediates their invasive phenotype; the blockade of HK2 represents a novel therapeutic strategy1.
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Succinate uptake via succinate receptor GPR91 induces an angiogenic phenotype in endothelial cells through hypoxia-inducible factor 1α-mediated vascular endothelial growth factor secretion, leading to increased migration, invasion and vessel sprouting2.
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In rheumatoid arthritis and coronary artery disease, macrophages have increased metabolic activity, a process mediated by glycogen synthase kinase 3β that depends on endoplasmic-reticulum-to-mitochondria calcium transport3.
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References
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Zeisbrich, M. et al. Hypermetabolic macrophages in rheumatoid arthritis and coronary artery disease due to glycogen synthase kinase 3b inactivation. Ann. Rheum. Dis. 77, 1053–1062 (2018).
McGarry, T. et al. Resolution of TLR2-induced inflammation through manipulation of metabolic pathways in rheumatoid arthritis. Sci. Rep. 7, 43165 (2017).
Takahashi, S. et al. Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res. Ther. 19, 76 (2017).
Garcia-Carbonell, R. et al. Critical role of glucose metabolism in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Rheumatol. 68, 1614–1626 (2016).
Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).
Biniecka, M. et al. Dysregulated bioenergetics: a key regulator of joint inflammation. Ann. Rheum. Dis. 75, 2192–2200 (2016).
Littlewood-Evans, A. et al. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J. Exp. Med. 213, 1655–1662 (2016).
Watanabe, R. et al. Glucose metabolism controls disease-specific signatures of macrophage effector functions. JCI Insight 3, 123047 (2018).
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McGarry, T., Fearon, U. Cell metabolism as a potentially targetable pathway in RA. Nat Rev Rheumatol 15, 70–72 (2019). https://doi.org/10.1038/s41584-018-0148-8
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DOI: https://doi.org/10.1038/s41584-018-0148-8
