Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis

Abstract

An increasing number of studies show how changes in intracellular metabolic pathways alter tumor and immune cell function. However, little information about metabolic changes in other cell types, including synovial fibroblasts, is available. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) are the most common cell type at the pannus–cartilage junction and contribute to joint destruction through their production of cytokines, chemokines, and matrix-degrading molecules and by migrating and invading joint cartilage. In this review, we show that these cells differ from healthy synovial fibroblasts, not only in their marker expression, proto-oncogene expression, or their epigenetic changes, but also in their intracellular metabolism. These metabolic changes must occur due to the stressful microenvironment of inflamed tissues, where concentrations of crucial nutrients such as glucose, glutamine, and oxygen are spatially and temporally heterogeneous. In addition, these metabolic changes will increase metabolite exchange between fibroblast and other synovial cells, which can potentially be activated. Glucose and phospholipid metabolism as well as bioactive lipids, including sphingosine-1-phosphate and lysophosphatidic acid, among others, are involved in FLS activation. These metabolic changes likely contribute to FLS involvement in aspects of immune response initiation or abnormal immune responses and strongly contribute to joint destruction.

Interactions between rheumatoid arthritis synovial fibroblast migration and endothelial cells

“…RASF were able to adhere to E‐selectin‐ but not P‐selectin‐coated capillaries to a higher degree than OASF. As a result of the preactivated state of RASF, for example because of epigenetic modifications and altered metabolism of RASF, they usually show a higher reactivity and matrix adhesion than OASF and an increased cartilage invasive and destructive potential. RASF adhesion to EC was significantly higher after TNFα activation of EC.…”

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

“…Directly targeting specific metabolic pathways has been demonstrated both in in-vitro and in-vivo models of arthritis where blockade of key glycolytic enzymes inhibits proinflammatory mechanisms [21,30,55,97]. Targeting metabolic intermediates including lactate acid, succinate, citrate, itaconate and lipids are also promising therapeutic avenues, where their cellular accumulation regulates synovial fibroblast invasiveness [21], T cell differentiation and migration [28,31,34], in addition to macrophage polarization [54].…”

Immune cell metabolism in autoimmunity

“…2DG-treated K/BXN mice also showed a reduced disease severity, in association with a decreased T and B cell metabolism and a reduced activation of both adaptive and innate immune cells [38]. In the same RA model, reducing glycolysis by targeting hexokinase (HK) showed beneficial effects by decreasing the activation of fibroblast-like synoviocytes [39]. Contrary to murine RA T cells and synoviocytes, glycolysis is reduced in the CD4 + T cells from RA patients, which develop a hyper-reduced state due to an over-active pentose phosphate pathway (PPP) [40].…”