Metabolites as drivers and targets in rheumatoid arthritis

The adverse microenvironment of the RA inflamed joint forces cells to switch their metabolic pathways in order to sustain their pathogenic activated status. Metabolites act as central hubs influencing multiple cellular functions and signaling pathways that further drive inflammation. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by neovascularization, 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 result 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 signalling 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 HIF1alpha 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.

Automated summary

The adverse microenvironment in RA inflamed joints causes cells to switch their metabolic pathways, leading to increased inflammation. Metabolites act as central hubs influencing multiple cellular functions and signaling pathways, shaping the inflammatory phenotype of immune cell subsets and potentially serving as therapeutic targets.