Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

Abstract

Rheumatoid arthritis is characterized by synovial proliferation, neovascularization and leucocyte extravasation leading to joint destruction and functional disability. The blood vessels in the inflamed synovium are highly dysregulated, resulting in poor delivery of oxygen; this, along with the increased metabolic demand of infiltrating immune cells and inflamed resident cells, results in the lack of key nutrients at the site of inflammation. In these adverse conditions synovial cells must adapt to generate sufficient energy to support their proliferation and activation status, and thus switch their cell metabolism from a resting regulatory state to a highly metabolically active state. This alters redox-sensitive signalling pathways and also results in the accumulation of metabolic intermediates which, in turn, can act as signalling molecules that further exacerbate the inflammatory response. The RA synovium is a multi-cellular tissue, and while many cell types interact to promote the inflammatory response, their metabolic requirements differ. Thus, understanding the complex interplay between hypoxia-induced signalling pathways, metabolic pathways and the inflammatory response will provide better insight into the underlying mechanisms of disease pathogenesis.

Keywords: arthritis (including rheumatoid arthritis); autoimmunity; inflammation.

Figure 1

Schematic illustration of the key metabolic pathways. Glucose enters the cell via glucose transporters and enters the glycolytic pathway. Hexokinase 2 (HK2) converts glucose into glucose 6‐phosphate dehydrogenase (G6PD). Glycolysis generates pyruvate from glucose with the help of pyruvate kinase M2 (PKM2). This process generates energy in the form of adenosine triphosphate (ATP). Pyruvate is then either converted to lactate and secreted out of the cell or decarboxylated by pyruvate dehydrogenase and converted to acetyl CoA, which enters the tricarboxylic acid (TCA) cycle. The TCA cycle generates nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FADH2) to feed into the electron transport chain (ETC), which produces 36 molecules of ATP. Glycolysis also feeds into the pentose phosphate pathway (PPP) to produce ribose, NADPH and amino acids. Amino acid metabolism can also feed into the TCA cycle to drive ATP production by the ETC. TCA intermediate citrate drives fatty acid synthesis while fatty acid oxidation drives TCA cycle further by generating acetyl CoA.

Figure 2

Schematic illustration of the glycolytic switch in different cell types. The hypoxic conditions of the synovial joint drives hypoxia‐inducible factor 1‐alpha (HIF‐1a)‐induced glycolysis in some of the major cell types of the synovium. HIF‐1a induces expression of some of the key molecular switches to encode proinflammatory and pro‐glycolytic mechanisms. Specifically, 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3) is up‐regulated in endothelial cells and synovial fibroblasts in response to hypoxia. The mammalian target of rapamycin (mTOR) pathway is also involved in synovial fibroblast activation. Pyruvate dehydrogenase (PKM2) plays a central role in the metabolic switch observed in inflammatory macrophages and activated monocytes. DC metabolism can be directed by protein kinase B (AKT) signalling pathways in early activation while mTOR‐mediated induction of inducible nitric oxide synthase (iNOS) is important during later stages of DC activation, while glucose‐6‐phosphate dehydrogenase (G6PD) and PFKFB3 are key players in the metabolic switch observed in effector T cells.