Cytosolic Phospholipase A2α Gene Silencing in the Myeloid Lineage Alters Development of Th1 Responses and Reduces Disease Severity in Collagen-Induced Arthritis
Cytosolic Phospholipase A2α Gene Silencing in the Myeloid Lineage Alters Development of Th1 Responses and Reduces Disease Severity in Collagen-Induced Arthritis
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DOI：
10.1002/art.30174
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发表时间：
2011-03-01
影响因子：
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通讯作者：
Davignon, J. -L.
中科院分区：
文献类型：
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作者：
Courties, G.;Baron, M.;Davignon, J. -L.
客观的。多项证据表明胞质磷脂酶 A(2)α (cPLA(2)α) 是炎症性疾病（包括类风湿性关节炎）中的关键酶。由于来自骨髓室的细胞调节局部和全身疾病发病机制，本研究旨在检查 cPLA(2)α 抑制对实验性关节炎的影响，使用通过 RNA 干扰 (RNAi) 专门针对单核细胞功能定制的递送系统。方法。患有胶原诱导性关节炎 (CIA) 的小鼠静脉注射抗 cPLA(2)α 小干扰 RNA (siRNA) 序列 (siPLA2)，该序列与 RPR209120/DOPE 阳离子脂质体和载体 DNA 配制为脂质复合物。评估关节炎症的临床过程，并通过测量 T 辅助细胞频率和细胞因子表达来分析免疫平衡。还进行了 siRNA 的生物分布研究。结果。与对照动物的研究结果相比，每周全身注射 siPLA2 lipoplexes 在预防和治疗环境中均显着降低了 CIA 的发生率和严重程度。炎症和软骨损伤的组织学评分降低。临床效果与局部抑制肿瘤坏死因子α分泌以及降低cPLA(2)α表达和活性相关。 siPLA2 lipoplexes 能够在从脾脏中回收的 CD11b+ 细胞中触发体内 RNAi 介导的 cPLA(2)alpha 基因沉默。虽然治疗对抗 II 型胶原蛋白（抗 CII）抗体没有影响，但引流淋巴结细胞中产生干扰素 γ 的 CII 特异性 T 辅助细胞减少，但不减少白细胞介素 17。结论。我们的研究结果表明，CD11b+细胞中系统性RNAi介导的cPLA(2)α基因沉默可有效治疗CIA，并且Th1抑制是潜在的潜在机制之一，而Th17抑制则不然。
Objective. Several lines of evidence implicate cytosolic phospholipase A(2)alpha (cPLA(2)alpha) as a critical enzyme in inflammatory disorders, including rheumatoid arthritis. Since cells from the myeloid compartment regulate local and systemic disease pathogenesis, the present study was undertaken to examine the effect of cPLA(2)alpha inhibition in experimental arthritis, using a delivery system tailored to target monocyte functions by RNA interference (RNAi).Methods. Mice with collagen-induced arthritis (CIA) were injected intravenously with an anti-cPLA(2)alpha small interfering RNA (siRNA) sequence (siPLA2) formulated as lipoplexes with the RPR209120/DOPE cationic liposome and a carrier DNA. The clinical course of joint inflammation was assessed, and the immunologic balance was analyzed by measuring T helper cell frequencies and cytokine expression. Biodistribution studies of siRNA were also performed.Results. Weekly systemic injection of siPLA2 lipoplexes significantly reduced the incidence and severity of CIA, in both preventive and curative settings, as compared with findings in control animals. Histologic scores for inflammation and cartilage damage were reduced. The clinical effect was associated with local inhibition of tumor necrosis factor alpha secretion and lower cPLA(2)alpha expression and activity. The siPLA2 lipoplexes enabled triggering of in vivo RNAi-mediated gene silencing of cPLA(2)alpha in CD11b+ cells recovered from the spleen. While the treatment had no effect on anti-type II collagen (anti-CII) antibodies, CII-specific T helper cells producing interferon-gamma, but not interleukin-17, in draining lymph node cells were decreased.Conclusion. Our findings indicate that systemic RNAi-mediated cPLA(2)alpha gene silencing in CD11b+ cells is effective in the treatment of CIA, and Th1 suppression is one of the potential underlying mechanisms, whereas Th17 suppression is not.