Metabolites as drivers and targets in rheumatoid arthritis

Abstract

Rheumatoid Arthritis is a chronic autoimmune disease characterised by neovascularisation, immune cell infiltration and synovial hyperplasia, which leads to degradation of articular cartilage and bone, and subsequent functional disability. Dysregulated angiogenesis, synovial hypoxia and immune cell infiltration results in a ‘bioenergetic crisis’ in the inflamed joint which further exacerbates synovial invasiveness. Several studies have examined this vicious cycle between metabolism, immunity and inflammation and the role metabolites play in these interactions. To add to this complexity the inflamed synovium is a multicellular tissue with many cellular subsets having different metabolic requirements. Metabolites can shape the inflammatory phenotype of immune cell subsets during disease and act as central signaling hubs. In the RA joint the increased energy demand of stromal and immune cells leads to the accumulation of metabolites such as lactate, citrate, and succinate as well as adipocytokines which can regulate downstream signalling pathways. Transcription factors such as HIF1ɑ and mTOR can act as metabolic sensors to activate synovial cells and drive pro-inflammatory effector function, thus perpetuating chronic inflammation further. These metabolic intermediates may be potential therapeutic targets and so understanding the complex interplay between metabolites and synovial cells in RA may allow for identification of novel therapeutic strategies but also may provide significant insight into the underlying mechanisms of disease pathogenesis.

Metabolites: fuelling the immune response

“…In recent years, multiple studies have addressed autoimmune disorders from an immunometabolic perspective describing how dysregulated metabolism in immune cells can be a trigger of the disorder. In their review, Hanlon et al [ 12 ] discuss the role of metabolites in rheumatoid arthritis (RA). RA is a chronic autoimmune disorder, characterized by progressive degradation of articular cartilage and bone, resulting in functional disability.…”

Gut-joint axis: Gut dysbiosis can contribute to the onset of rheumatoid arthritis via multiple pathways

“…AhR signaling contributes to immune homeostasis by modulating T cell differentiation. Indole derivatives are implicated in immune cell maturation and promote Treg differentiation while suppressing Th17 differentiation (Wang et al, 2019a;Yu et al, 2021;Hanlon et al, 2022;Yang et al, 2022). AhR expression and activation in DCs or T cells translate into Treg cellmediated immunoregulatory effects, which dampen immune responses.…”

Solute carrier nutrient transporters in rheumatoid arthritis fibroblast-like synoviocytes

“…Several studies have been conducted on the role of metabolism in RA pathogenesis. Different cell types in the inflamed synovium require various metabolites in order to meet energy demands including lactate, citrate, and succinate ( 5 , 19 , 20 ). This metabolic change is also accompanied by differences in immunity and inflammation and affects both stromal and immune cells ( 21 ).…”