Metabolic Profiling of Rheumatoid Arthritis Neutrophils Reveals Altered Energy Metabolism That Is Not Affected by JAK Inhibition.
Metabolic Profiling of Rheumatoid Arthritis Neutrophils Reveals Altered Energy Metabolism That Is Not Affected by JAK Inhibition.
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风湿性关节炎中性粒细胞的代谢谱揭示了不受JAK抑制影响的能量代谢改变。
DOI：
10.3390/metabo12070650
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发表时间：
2022-07-15
期刊：
影响因子：
4.1
通讯作者：
中科院分区：
文献类型：
--
作者：
中性粒细胞在类风湿关节炎(RA)的病理生理学中起着关键作用，类风湿关节炎(RA)中ROS和蛋白水解酶的释放直接导致关节和组织的损伤。JAK(Janus Kinase，JAK)抑制剂药物可以调节中性粒细胞功能，包括托法替尼和巴利西替尼，这两种药物都是临床上治疗类风湿关节炎的有效药物。然而，临床试验报告了在治疗过程中感染率增加和一过性中性粒细胞减少。JAK抑制剂在作用方式、疗效和安全性方面的细微差异一直是许多临床试验和系统综述的首要研究课题，以期为患者提供更精确和有针对性的治疗。本研究的目的是确定正常人和RA患者中性粒细胞代谢组的差异，以及不同JAK抑制剂对正常人和RA中性粒细胞代谢组的影响。将分离自健康对照组(HC)和类风湿关节炎(RA)患者(7例)的中性粒细胞分别与巴利替尼、托法替尼或PAN-JAK抑制剂(均为200 ng/mL)孵育2 h，提取代谢物，用核磁共振(1H核磁共振)研究其代谢变化。多变量分析和机器学习模型显示，在能量代谢产物(ATP、ADP、GTP和葡萄糖)的驱动下，RA中性粒细胞在0h的代谢模式与HC不同(F1评分=86.7%)。用JAK抑制剂处理后，中性粒细胞代谢组无明显变化。然而，JAK抑制剂显著抑制了ROS的产生，而巴利西尼则减少了净产生(p<；0.05)。JAK抑制剂对细菌的杀伤作用不受影响，说明JAK抑制剂对中性粒细胞的作用可以抑制RA关节损伤，而不损害宿主防御。这项研究强调了RA中性粒细胞能量代谢的改变，这可能解释了炎症性疾病中中性粒细胞调节失调的原因。
Neutrophils play a key role in the pathophysiology of rheumatoid arthritis (RA) where release of ROS and proteases directly causes damage to joints and tissues. Neutrophil function can be modulated by Janus Kinase (JAK) inhibitor drugs, including tofacitinib and baricitinib, which are clinically effective treatments for RA. However, clinical trials have reported increased infection rates and transient neutropenia during therapy. The subtle differences in the mode of action, efficacy and safety of JAK inhibitors have been the primary research topic of many clinical trials and systematic reviews, to provide a more precise and targeted treatment to patients. The aim of this study was to determine both the differences in the metabolome of neutrophils from healthy controls and people with RA, and the effect of different JAK inhibitors on the metabolome of healthy and RA neutrophils. Isolated neutrophils from healthy controls (HC) (n = 6) and people with RA (n = 7) were incubated with baricitinib, tofacitinib or a pan-JAK inhibitor (all 200 ng/mL) for 2 h. Metabolites were extracted, and 1H nuclear magnetic resonance (NMR) was applied to study the metabolic changes. Multivariate analyses and machine learning models showed a divergent metabolic pattern in RA neutrophils compared to HC at 0 h (F1 score = 86.7%) driven by energy metabolites (ATP, ADP, GTP and glucose). No difference was observed in the neutrophil metabolome when treated with JAK inhibitors. However, JAK inhibitors significantly inhibited ROS production and baricitinib decreased NET production (p < 0.05). Bacterial killing was not impaired by JAK inhibitors, indicating that the effect of JAK inhibitors on neutrophils can inhibit joint damage in RA without impairing host defence. This study highlights altered energy metabolism in RA neutrophils which may explain the cause of their dysregulation in inflammatory disease.
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3.6
作者：
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