Molecular Rheumatology, Trinity Biomedical Sciences Institute, TCD, Dublin, Ireland.
EULAR Centre of Excellence, Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Dublin, Ireland.
Nat Rev Rheumatol. 2022 Jul;18(7):398-414. doi: 10.1038/s41584-022-00771-x. Epub 2022 Apr 19.
Activation of endothelium and immune cells is fundamental to the initiation of autoimmune diseases such as rheumatoid arthritis (RA), and it results in trans-endothelial cell migration and synovial fibroblast proliferation, leading to joint destruction. In RA, the synovial microvasculature is highly dysregulated, resulting in inefficient oxygen perfusion to the synovium, which, along with the high metabolic demands of activated immune and stromal cells, leads to a profoundly hypoxic microenvironment. In inflamed joints, infiltrating immune cells and synovial resident cells have great requirements for energy and nutrients, and they adapt their metabolic profiles to generate sufficient energy to support their highly activated inflammatory states. This shift in metabolic capacity of synovial cells enables them to produce the essential building blocks to support their proliferation, activation and invasiveness. Furthermore, it results in the accumulation of metabolic intermediates and alteration of redox-sensitive pathways, affecting signalling pathways that further potentiate the inflammatory response. Importantly, the inflamed synovium is a multicellular tissue, with cells differing in their metabolic requirements depending on complex cell-cell interactions, nutrient supply, metabolic intermediates and transcriptional regulation. Therefore, understanding the complex interplay between metabolic and inflammatory pathways in synovial cells in RA will provide insight into the underlying mechanisms of disease pathogenesis.
内皮细胞和免疫细胞的激活是引发类风湿关节炎 (RA) 等自身免疫性疾病的基础，它导致跨内皮细胞迁移和滑膜成纤维细胞增殖，从而导致关节破坏。在 RA 中，滑膜微血管系统高度失调，导致滑膜氧灌注效率低下，加上激活的免疫细胞和基质细胞的高代谢需求，导致缺氧微环境。在发炎的关节中，浸润的免疫细胞和滑膜固有细胞对能量和营养物质有很高的需求，它们会调整其代谢特征，以产生足够的能量来支持其高度激活的炎症状态。滑膜细胞代谢能力的这种转变使它们能够产生支持其增殖、激活和侵袭所需的基本构建块。此外，它还导致代谢中间产物的积累和氧化还原敏感途径的改变，影响信号通路，进一步增强炎症反应。重要的是，发炎的滑膜是一种多细胞组织，细胞的代谢需求因复杂的细胞-细胞相互作用、营养供应、代谢中间产物和转录调节而有所不同。因此，了解 RA 中滑膜细胞代谢和炎症途径之间的复杂相互作用将为疾病发病机制的潜在机制提供深入的了解。
