Abstract：
BACKGROUND: Hypocortisolemia is associated with increased expression of NR3C1 (glucocorticoid receptor, GR) in blood cells. As endogenous cortisol production is decreased in some RA patients, we tested the hypothesis that GR may be aberrantly expressed in rheumatoid synovium.
METHODS: We defined the cellular pattern of NR3C1 synovial expression using human and mouse single-cell RNA-sequencing data. Bulk synovial RNA-sequencing data from early (n = 57) or established (n = 94) RA were compared to osteoarthritis (n = 22) and healthy synovium (n = 28).
RESULTS: GR was expressed in all synovial cell types in both human and experimental arthritis. GR synovial expression, as well as 11β-HSD1/11β-HSD2 enzyme ratio, were higher in RA than healthy and osteoarthritic tissue, regardless of disease duration or treatment. Given that GR expression varied across samples, we searched for differences between RA patients with higher versus lower GR expression. Indeed, the synovial transcriptome of RA patients with high versus low GR expression (1st quartile, 30,517 ± 4876 vs. 4th quartile, 19,382 ± 2523 normalized counts) was enriched for proinflammatory gene-sets, including \'inflammatory response\', \'IFN-γ response\' and \'IL6/JAK/STAT3 signalling\'. High synovial GR expression was also associated with increased JAK2 and PTPRK expression, denoting activation of the proinflammatory sublining fibroblasts. In contrast, low GR expression was associated with increased COMP and COL6A2 expression, denoting a resting synovial state.
CONCLUSIONS: GR is overexpressed in the synovium of some RA patients in association with proinflammatory gene expression and activated sublining fibroblast status. Further studies should examine whether GR overexpression may act as a compensatory mechanism sensitizing synovial tissue to glucocorticoid action in RA.
METHODS: We defined the cellular pattern of NR3C1 synovial expression using human and mouse single-cell RNA-sequencing data. Bulk synovial RNA-sequencing data from early (n = 57) or established (n = 94) RA were compared to osteoarthritis (n = 22) and healthy synovium (n = 28).
RESULTS: GR was expressed in all synovial cell types in both human and experimental arthritis. GR synovial expression, as well as 11β-HSD1/11β-HSD2 enzyme ratio, were higher in RA than healthy and osteoarthritic tissue, regardless of disease duration or treatment. Given that GR expression varied across samples, we searched for differences between RA patients with higher versus lower GR expression. Indeed, the synovial transcriptome of RA patients with high versus low GR expression (1st quartile, 30,517 ± 4876 vs. 4th quartile, 19,382 ± 2523 normalized counts) was enriched for proinflammatory gene-sets, including \'inflammatory response\', \'IFN-γ response\' and \'IL6/JAK/STAT3 signalling\'. High synovial GR expression was also associated with increased JAK2 and PTPRK expression, denoting activation of the proinflammatory sublining fibroblasts. In contrast, low GR expression was associated with increased COMP and COL6A2 expression, denoting a resting synovial state.
CONCLUSIONS: GR is overexpressed in the synovium of some RA patients in association with proinflammatory gene expression and activated sublining fibroblast status. Further studies should examine whether GR overexpression may act as a compensatory mechanism sensitizing synovial tissue to glucocorticoid action in RA.
摘要：
背景：低皮质醇血症与NR3C1（糖皮质激素受体，血细胞中的GR)。由于内源性皮质醇的产生在一些RA患者中减少，我们检验了GR可能在类风湿滑膜中异常表达的假设。
方法：我们使用人和小鼠单细胞RNA测序数据定义了NR3C1滑膜表达的细胞模式。将早期（n=57）或已建立（n=94）RA的大量滑膜RNA测序数据与骨关节炎（n=22）和健康滑膜（n=28）进行比较。
结果：GR在人和实验性关节炎的所有滑膜细胞类型中均有表达。滑膜GR表达,以及11β-HSD1/11β-HSD2酶比，RA高于健康和骨关节炎组织，无论疾病持续时间或治疗。鉴于GR表达在不同样本中变化，我们搜索了GR表达较高和较低的RA患者之间的差异.的确,GR高表达与低表达的RA患者的滑膜转录组(第1四分位数，30,517±4876vs.第四四分位数,19,382±2523标准化计数）富集了促炎基因集，包括“炎症反应”，“IFN-γ应答”和“IL6/JAK/STAT3信号”。高滑膜GR表达也与JAK2和PTPRK表达增加相关，表示促炎性下层成纤维细胞的激活。相比之下,低GR表达与COMP和COL6A2表达增加相关，表示静息滑膜状态。
结论：GR在一些RA患者的滑膜中过表达，与促炎基因表达和激活的成纤维细胞功能相关。进一步的研究应检查GR过表达是否可以作为补偿机制，使滑膜组织对糖皮质激素作用敏感。
方法：我们使用人和小鼠单细胞RNA测序数据定义了NR3C1滑膜表达的细胞模式。将早期（n=57）或已建立（n=94）RA的大量滑膜RNA测序数据与骨关节炎（n=22）和健康滑膜（n=28）进行比较。
结果：GR在人和实验性关节炎的所有滑膜细胞类型中均有表达。滑膜GR表达,以及11β-HSD1/11β-HSD2酶比，RA高于健康和骨关节炎组织，无论疾病持续时间或治疗。鉴于GR表达在不同样本中变化，我们搜索了GR表达较高和较低的RA患者之间的差异.的确,GR高表达与低表达的RA患者的滑膜转录组(第1四分位数，30,517±4876vs.第四四分位数,19,382±2523标准化计数）富集了促炎基因集，包括“炎症反应”，“IFN-γ应答”和“IL6/JAK/STAT3信号”。高滑膜GR表达也与JAK2和PTPRK表达增加相关，表示促炎性下层成纤维细胞的激活。相比之下,低GR表达与COMP和COL6A2表达增加相关，表示静息滑膜状态。
结论：GR在一些RA患者的滑膜中过表达，与促炎基因表达和激活的成纤维细胞功能相关。进一步的研究应检查GR过表达是否可以作为补偿机制，使滑膜组织对糖皮质激素作用敏感。
