Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：在炎症性疾病如类风湿性关节炎（RA）中，类固醇代谢是介导免疫调节性糖皮质激素和性类固醇作用的重要组成部分。然而,在关键的白细胞群体如巨噬细胞中,细胞类固醇代谢的调节和功能仍不明确.在这项研究中,在RA巨噬细胞中评估了整体类固醇代谢的炎症调节.
方法：来自RA滑膜巨噬细胞的BulkRNA-seq数据用于评估编码类固醇代谢和信号传导中关键酶的转录本。在滑液中评估代谢的变化，与疾病活动的测量相关，并在原代巨噬细胞培养物中进行了功能验证。
结果：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的基因的变化。这些与疾病活动相关，有利于增加糖皮质激素和雄激素水平。滑液11β-HSD1活性与局部炎症介质（TNFα，IL-6,IL-17),而11β-HSD1、SRD5A1和AKR1C3活性与疾病和患者疼痛的全身测量相关(ESR，DAS28ESR,全球疾病活动)。酶活性的变化在体外炎性激活的巨噬细胞中很明显，并揭示了11β-HSD1的新型雄激素激活作用。一起,糖皮质激素和雄激素的增加能够抑制巨噬细胞和成纤维细胞样滑膜细胞的炎症。
结论：这项研究强调了滑膜的炎性极化巨噬细胞中雄激素和糖皮质激素活化的显着增加，有助于局部抑制炎症。绝经后妇女中无活性类固醇前体的减少可能导致这一过程的紊乱。导致疾病发病率和严重程度增加。
方法：来自RA滑膜巨噬细胞的BulkRNA-seq数据用于评估编码类固醇代谢和信号传导中关键酶的转录本。在滑液中评估代谢的变化，与疾病活动的测量相关，并在原代巨噬细胞培养物中进行了功能验证。
结果：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的基因的变化。这些与疾病活动相关，有利于增加糖皮质激素和雄激素水平。滑液11β-HSD1活性与局部炎症介质（TNFα，IL-6,IL-17),而11β-HSD1、SRD5A1和AKR1C3活性与疾病和患者疼痛的全身测量相关(ESR，DAS28ESR,全球疾病活动)。酶活性的变化在体外炎性激活的巨噬细胞中很明显，并揭示了11β-HSD1的新型雄激素激活作用。一起,糖皮质激素和雄激素的增加能够抑制巨噬细胞和成纤维细胞样滑膜细胞的炎症。
结论：这项研究强调了滑膜的炎性极化巨噬细胞中雄激素和糖皮质激素活化的显着增加，有助于局部抑制炎症。绝经后妇女中无活性类固醇前体的减少可能导致这一过程的紊乱。导致疾病发病率和严重程度增加。
