Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
School of Biomedical Sciences. Institute of Clinical Sciences, University of Birmingham, Birmingham, UK.
J Autoimmun. 2024 Jul;147:103263. doi: 10.1016/j.jaut.2024.103263. Epub 2024 Jun 8.
In inflammatory diseases such as rheumatoid arthritis (RA), steroid metabolism is a central component mediating the actions of immuno-modulatory glucocorticoids and sex steroids. However, the regulation and function of cellular steroid metabolism within key leukocyte populations such as macrophages remain poorly defined. In this study, the inflammatory regulation of global steroid metabolism was assessed in RA macrophages.
Bulk RNA-seq data from RA synovial macrophages was used to assess transcripts encoding key enzymes in steroid metabolism and signalling. Changes in metabolism were assessed in synovial fluids, correlated to measures of disease activity and functionally validated in primary macrophage cultures.
RNA-seq revealed a unique pattern of differentially expressed genes, including changes in genes encoding the enzymes 11β-HSD1, SRD5A1, AKR1C2 and AKR1C3. These correlated with disease activity, favouring increased glucocorticoid and androgen levels. Synovial fluid 11β-HSD1 activity correlated with local inflammatory mediators (TNFα, IL-6, IL-17), whilst 11β-HSD1, SRD5A1 and AKR1C3 activity correlated with systemic measures of disease and patient pain (ESR, DAS28 ESR, global disease activity). Changes in enzyme activity were evident in inflammatory activated macrophages in vitro and revealed a novel androgen activating role for 11β-HSD1. Together, increased glucocorticoids and androgens were able to suppress inflammation in macrophages and fibroblast-like-synoviocytes.
This study underscores the significant increase in androgen and glucocorticoid activation within inflammatory polarized macrophages of the synovium, contributing to local suppression of inflammation. The diminished profile of inactive steroid precursors in postmenopausal women may contribute to disturbances in this process, leading to increased disease incidence and severity.
在类风湿关节炎（RA）等炎症性疾病中，类固醇代谢是调节免疫调节糖皮质激素和性激素作用的核心组成部分。然而，细胞类固醇代谢在关键白细胞群体（如巨噬细胞）中的调节和功能仍未得到明确界定。在这项研究中，评估了 RA 巨噬细胞中类固醇代谢的整体炎症调节。
使用 RA 滑膜巨噬细胞的批量 RNA-seq 数据评估类固醇代谢和信号转导中关键酶的转录本。在滑膜液中评估代谢变化，与疾病活动的测量值相关，并在原代巨噬细胞培养物中进行功能验证。
RNA-seq 揭示了差异表达基因的独特模式，包括编码酶 11β-HSD1、SRD5A1、AKR1C2 和 AKR1C3 的基因变化。这些变化与疾病活动相关，有利于增加糖皮质激素和雄激素水平。滑膜液 11β-HSD1 活性与局部炎症介质（TNFα、IL-6、IL-17）相关，而 11β-HSD1、SRD5A1 和 AKR1C3 活性与系统性疾病和患者疼痛（ESR、DAS28 ESR、总体疾病活动）相关。在体外炎症激活的巨噬细胞中观察到酶活性的变化，并揭示了 11β-HSD1 的新型雄激素激活作用。总的来说，增加的糖皮质激素和雄激素能够抑制巨噬细胞和成纤维样滑膜细胞的炎症。
这项研究强调了炎症极化的滑膜巨噬细胞中雄激素和糖皮质激素激活的显著增加，有助于局部抑制炎症。绝经后女性中无活性类固醇前体的减少可能导致该过程紊乱，导致疾病发生率和严重程度增加。
