Rheumatoid arthritis CD14(+) monocytes display metabolic and inflammatory dysfunction, a phenotype that precedes clinical manifestation of disease.
Rheumatoid arthritis CD14(+) monocytes display metabolic and inflammatory dysfunction, a phenotype that precedes clinical manifestation of disease.
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DOI：
10.1002/cti2.1237
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发表时间：
2021
影响因子：
5.8
通讯作者：
Fearon U
中科院分区：
文献类型：
--
作者：
McGarry T;Hanlon MM;Marzaioli V;Cunningham CC;Krishna V;Murray K;Hurson C;Gallagher P;Nagpal S;Veale DJ;Fearon U
本研究调查了循环单核细胞的代谢活性及其对RA的促炎反应的影响，并探讨了这种表型是否在疾病临床表现之前就已经为炎症做好了准备。采集健康对照供者（HC）、高危个体（IAR）和RA患者的血液并分离CD14+单核细胞。流式细胞术检测血液及滑膜组织单核细胞频率。通过RT - PCR、Western blot、迁移试验、Seahorse - XFe技术、mitotracker试验和透射电镜对炎症反应和代谢分析±特异性抑制剂进行量化。对HC、IAR和RA滑膜组织进行转录组学分析。RA患者的CD14+单核细胞在刺激后呈高炎性，细胞因子/趋化因子的表达明显高于HC患者。LPS诱导的RA单核细胞迁移能力与RA滑膜组织单核细胞频率增加一致。RA CD14+单核细胞显示线粒体呼吸增强，生物发生和线粒体形态改变。此外，RA单核细胞显示关键糖酵解酶HIF1α、HK2和PFKFB3水平升高，并表现出对葡萄糖消耗的依赖，阻断葡萄糖消耗可消除促炎介质反应。阻断STAT3激活可抑制这种强制糖酵解通量，从而导致代谢重编程和炎症的消退。有趣的是，除了在IAR的滑膜组织中观察到增强的单核细胞基因特征外，这种高度活化的单核细胞表型在发展中的IAR中也很明显。RA CD14+单核细胞被代谢重新编程以持续诱导促炎反应，STAT3被确定为代谢功能障碍的分子调节因子。这种表型先于临床疾病发作，可能代表了疾病早期靶向治疗的潜在途径。在这项研究中，我们证明了类风湿性关节炎CD14+单核细胞在代谢上被重新编程以持续诱导促炎反应，这一效应是由STAT3信号介导的，并在临床疾病发作之前发生。
This study investigates the metabolic activity of circulating monocytes and their impact on pro‐inflammatory responses in RA and explores whether this phenotype is already primed for inflammation before clinical manifestations of disease. Blood was collected and CD14+ monocytes isolated from healthy control donors (HC), individuals at‐risk (IAR) and RA patients. Monocyte frequency in blood and synovial tissue was assessed by flow cytometry. Inflammatory responses and metabolic analysis ± specific inhibitors were quantified by RT‐PCR, Western blot, migration assays, Seahorse‐XFe‐technology, mitotracker assays and transmission electron microscopy. Transcriptomic analysis was performed on HC, IAR and RA synovial tissue. CD14+ monocytes from RA patients are hyper‐inflammatory following stimulation, with significantly higher expression of cytokines/chemokines than those from HC. LPS‐induced RA monocyte migratory capacity is consistent with increased monocyte frequency in RA synovial tissue. RA CD14+ monocytes show enhanced mitochondrial respiration, biogenesis and alterations in mitochondrial morphology. Furthermore, RA monocytes display increased levels of key glycolytic enzymes HIF1α, HK2 and PFKFB3 and demonstrate a reliance on glucose consumption, blockade of which abrogates pro‐inflammatory mediator responses. Blockade of STAT3 activation inhibits this forced glycolytic flux resulting in metabolic reprogramming and resolution of inflammation. Interestingly, this highly activated monocytic phenotype is evident in IAR of developing disease, in addition to an enhanced monocyte gene signature observed in synovial tissue from IAR. RA CD14+ monocytes are metabolically re‐programmed for sustained induction of pro‐inflammatory responses, with STAT3 identified as a molecular regulator of metabolic dysfunction. This phenotype precedes clinical disease onset and may represent a potential pathway for therapeutic targeting early in disease. In this study, we demonstrated that rheumatoid arthritis CD14+ monocytes are metabolically re‐programmed for sustained induction of pro‐inflammatory responses, an effect that is mediated by STAT3 signalling and precedes clinical disease onset.
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影响因子：
27.4
作者：
Gerlag DM;Raza K;van Baarsen LG;Brouwer E;Buckley CD;Burmester GR;Gabay C;Catrina AI;Cope AP;Cornelis F;Dahlqvist SR;Emery P;Eyre S;Finckh A;Gay S;Hazes JM;van der Helm-van Mil A;Huizinga TW;Klareskog L;Kvien TK;Lewis C;Machold KP;Rönnelid J;van Schaardenburg D;Schett G;Smolen JS;Thomas S;Worthington J;Tak PP
通讯作者：
Tak PP
影响因子：
3.7
作者：
Ates, A;Kinikli, G;Duman, M
通讯作者：
Duman, M
影响因子：
27.4
作者：
Harty, Leonard C.;Biniecka, Monika;Fearon, Ursula
通讯作者：
Fearon, Ursula
影响因子：
--
作者：
Gent, Yoony Y. J.;Voskuyl, Alexandre E.;van der Laken, Conny J.
通讯作者：
van der Laken, Conny J.
影响因子：
4.9
作者：
Cole S;Walsh A;Yin X;Wechalekar MD;Smith MD;Proudman SM;Veale DJ;Fearon U;Pitzalis C;Humby F;Bombardieri M;Axel A;Adams H 3rd;Chiu C;Sharp M;Alvarez J;Anderson I;Madakamutil L;Nagpal S;Guo Y
通讯作者：
Guo Y