Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.
Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen, Guangdong, China.
Clin Transl Med. 2022 Dec;12(12):e1148. doi: 10.1002/ctm2.1148.
Rheumatoid arthritis (RA) is a chronic autoimmune disease. We previously revealed that the natural compound artemisitene (ATT) exhibits excellent broad anticancer activities without toxicity on normal tissues. Nevertheless, the effect of ATT on RA is undiscovered. Herein, we aim to study the effect and potential mechanism of ATT on RA management.
A collagen-induced arthritis (CIA) mouse model was employed to confirm the anti-RA potential of ATT. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays, cell cycle and apoptosis analysis, immunofluorescence, migration and invasion assays, quantitative real-time PCR (RT-qPCR), Western blot, RNA-sequencing (RNA-seq) analysis, plasmid construction and lentivirus infection, and methylated RNA immunoprecipitation and chromatin immunoprecipitation assays, were carried out to confirm the effect and potential mechanism of ATT on RA management.
ATT relieved CIA in mice. ATT inhibited proliferation and induced apoptosis of RA-fibroblast-like synoviocytes (FLSs). ATT restrained RA-FLSs migration and invasion via suppressing epithelial-mesenchymal transition. RNA-sequencing analysis and bioinformatics analysis identified intercellular adhesion molecule 2 (ICAM2) as a promoter of RA progression in RA-FLSs. ATT inhibits RA progression by suppressing ICAM2/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/p300 pathway in RA-FLSs. Moreover, ATT inhibited methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine methylation of ICAM2 mRNA in RA-FLSs. Interestingly, p300 directly facilitated METTL3 transcription, which could be restrained by ATT in RA-FLSs. Importantly, METTL3, ICAM2 and p300 expressions in synovium tissues of RA patients were related to clinical characteristics and therapy response.
We provided strong evidence that ATT has therapeutic potential for RA management by suppressing proliferation, migration and invasion, in addition to inducing apoptosis of RA-FLSs through modulating METTL3/ICAM2/PI3K/AKT/p300 feedback loop, supplying the fundamental basis for the clinical application of ATT in RA therapy. Moreover, METTL3, ICAM2 and p300 might serve as biomarkers for the therapy response of RA patients.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病。我们之前发现，天然化合物青蒿素（ATT）在正常组织中没有毒性的情况下，对多种癌症具有优异的广谱抗癌活性。然而，ATT 对 RA 的作用尚未被发现。在此，我们旨在研究 ATT 对 RA 管理的作用和潜在机制。
采用胶原诱导关节炎（CIA）小鼠模型证实 ATT 的抗 RA 潜力。细胞计数试剂盒-8（CCK-8）和 5-乙炔基-2'-脱氧尿苷（EdU）检测、细胞周期和凋亡分析、免疫荧光、迁移和侵袭检测、实时定量 PCR（RT-qPCR）、Western blot、RNA 测序（RNA-seq）分析、质粒构建和慢病毒感染、甲基化 RNA 免疫沉淀和染色质免疫沉淀检测，用于确认 ATT 对 RA 管理的作用和潜在机制。
ATT 缓解了 CIA 小鼠的症状。ATT 抑制 RA 成纤维样滑膜细胞（FLS）的增殖并诱导其凋亡。ATT 通过抑制上皮间质转化来抑制 RA-FLS 的迁移和侵袭。RNA-seq 分析和生物信息学分析确定细胞间黏附分子 2（ICAM2）是 RA-FLS 中 RA 进展的促进因子。ATT 通过抑制 RA-FLS 中的细胞间黏附分子 2/磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）/p300 通路来抑制 RA 进展。此外，ATT 抑制了 RA-FLS 中甲基转移酶样 3（METTL3）介导的 ICAM2 mRNA 的 N6-甲基腺苷甲基化。有趣的是，p300 直接促进了 METTL3 的转录，而在 RA-FLS 中，ATT 可以抑制这种转录。重要的是，RA 患者滑膜组织中 METTL3、ICAM2 和 p300 的表达与临床特征和治疗反应有关。
我们提供了强有力的证据表明，ATT 通过抑制 RA-FLS 的增殖、迁移和侵袭，同时诱导其凋亡，从而具有治疗 RA 的潜力，通过调节 METTL3/ICAM2/PI3K/AKT/p300 反馈环。为 ATT 在 RA 治疗中的临床应用提供了基础。此外，METTL3、ICAM2 和 p300 可能作为 RA 患者治疗反应的生物标志物。
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