PDF(Pubmed)
Abstract：
UNASSIGNED: Distinct, disease-associated intracellular miRNA (miR) expression profiles have been observed in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients. Additionally, we have identified novel estrogenic responses in PBMCs from SLE patients and demonstrated that estrogen upregulates toll-like receptor (TLR)7 and TLR8 expression. TLR7 and TLR8 bind viral-derived single-stranded RNA to stimulate innate inflammatory responses, but recent studies have shown that miR-21, mir-29a, and miR-29b can also bind and activate these receptors when packaged and secreted in extracellular vesicles (EVs). The objective of this study was to evaluate the association of EV-encapsulated small RNA species in SLE and examine the therapeutic approach of miR inhibition in humanized mice.
UNASSIGNED: Plasma-derived EVs were isolated from SLE patients and quantified. RNA was then isolated and bulk RNA-sequencing reads were analyzed. Also, PBMCs from active SLE patients were injected into immunodeficient mice to produce chimeras. Prior to transfer, the PBMCs were incubated with liposomal EVs containing locked nucleic acid (LNA) antagonists to miR-21, mir-29a, and miR-29b. After three weeks, blood was collected for both immunophenotyping and cytokine analysis; tissue was harvested for histopathological examination.
UNASSIGNED: EVs were significantly increased in the plasma of SLE patients and differentially expressed EV-derived small RNA profiles were detected compared to healthy controls, including miR-21, mir-29a, and miR-29b. LNA antagonists significantly reduced proinflammatory cytokines and histopathological infiltrates in the small intestine, liver, and kidney, as demonstrated by H&E-stained tissue sections and immunohistochemistry measuring human CD3.
UNASSIGNED: These data demonstrate distinct EV-derived small RNA signatures representing SLE-associated biomarkers. Moreover, targeting upregulated EV-encapsulated miR signaling by antagonizing miRs that may bind to TLR7 and TLR8 reveals a novel therapeutic opportunity to suppress autoimmune-mediated inflammation and pathogenesis in SLE.
UNASSIGNED: Plasma-derived EVs were isolated from SLE patients and quantified. RNA was then isolated and bulk RNA-sequencing reads were analyzed. Also, PBMCs from active SLE patients were injected into immunodeficient mice to produce chimeras. Prior to transfer, the PBMCs were incubated with liposomal EVs containing locked nucleic acid (LNA) antagonists to miR-21, mir-29a, and miR-29b. After three weeks, blood was collected for both immunophenotyping and cytokine analysis; tissue was harvested for histopathological examination.
UNASSIGNED: EVs were significantly increased in the plasma of SLE patients and differentially expressed EV-derived small RNA profiles were detected compared to healthy controls, including miR-21, mir-29a, and miR-29b. LNA antagonists significantly reduced proinflammatory cytokines and histopathological infiltrates in the small intestine, liver, and kidney, as demonstrated by H&E-stained tissue sections and immunohistochemistry measuring human CD3.
UNASSIGNED: These data demonstrate distinct EV-derived small RNA signatures representing SLE-associated biomarkers. Moreover, targeting upregulated EV-encapsulated miR signaling by antagonizing miRs that may bind to TLR7 and TLR8 reveals a novel therapeutic opportunity to suppress autoimmune-mediated inflammation and pathogenesis in SLE.
摘要：
■区别，已经在系统性红斑狼疮(SLE)患者的外周血单核细胞(PBMC)中观察到疾病相关的细胞内miRNA(miR)表达谱。此外,我们在SLE患者的PBMC中发现了新的雌激素反应,并证明雌激素上调toll样受体(TLR)7和TLR8的表达.TLR7和TLR8结合病毒衍生的单链RNA刺激先天炎症反应，但是最近的研究表明miR-21，mir-29a，当包装和分泌在细胞外囊泡（EV）中时，miR-29b也可以结合和激活这些受体。这项研究的目的是评估EV封装的小RNA物种在SLE中的关联，并检查人源化小鼠中miR抑制的治疗方法。
■从SLE患者中分离血浆来源的EV并进行定量。然后分离RNA并分析大量RNA测序读数。此外，将来自活动性SLE患者的PBMC注射到免疫缺陷小鼠中以产生嵌合体。在转移之前,PBMC与含有miR-21，mir-29a的锁核酸（LNA）拮抗剂的脂质体EV一起孵育，和miR-29b。三周后,收集血液进行免疫表型分析和细胞因子分析;收集组织进行组织病理学检查.
■与健康对照相比，SLE患者血浆中的EV显着增加，并且检测到差异表达的EV衍生的小RNA谱，包括miR-21，mir-29a，和miR-29b。LNA拮抗剂显著降低了小肠中的促炎细胞因子和组织病理学浸润,肝脏,和肾脏，如通过H&E染色的组织切片和免疫组织化学测量人CD3所证明的。
■这些数据证明了代表SLE相关生物标志物的不同EV衍生的小RNA特征。此外，通过拮抗可能与TLR7和TLR8结合的miR靶向上调的EV封装的miR信号,揭示了在SLE中抑制自身免疫介导的炎症和发病机制的新治疗机会.
■从SLE患者中分离血浆来源的EV并进行定量。然后分离RNA并分析大量RNA测序读数。此外，将来自活动性SLE患者的PBMC注射到免疫缺陷小鼠中以产生嵌合体。在转移之前,PBMC与含有miR-21，mir-29a的锁核酸（LNA）拮抗剂的脂质体EV一起孵育，和miR-29b。三周后,收集血液进行免疫表型分析和细胞因子分析;收集组织进行组织病理学检查.
■与健康对照相比，SLE患者血浆中的EV显着增加，并且检测到差异表达的EV衍生的小RNA谱，包括miR-21，mir-29a，和miR-29b。LNA拮抗剂显著降低了小肠中的促炎细胞因子和组织病理学浸润,肝脏,和肾脏，如通过H&E染色的组织切片和免疫组织化学测量人CD3所证明的。
■这些数据证明了代表SLE相关生物标志物的不同EV衍生的小RNA特征。此外，通过拮抗可能与TLR7和TLR8结合的miR靶向上调的EV封装的miR信号,揭示了在SLE中抑制自身免疫介导的炎症和发病机制的新治疗机会.
