Therapeutic siRNA silencing in inflammatory monocytes in mice.
Therapeutic siRNA silencing in inflammatory monocytes in mice.
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DOI：
10.1038/nbt.1989
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发表时间：
2011-10-09
影响因子：
46.9
通讯作者：
中科院分区：
文献类型：
--
作者：
炎性单核细胞-而不是非炎性亚群-依赖于趋化因子受体CCR 2分布到受损组织并刺激疾病进展。精确的治疗靶向这种炎症单核细胞亚群可以节省先天免疫的基本功能，以维持稳态，从而限制不必要的影响。在这里，我们开发了靶向炎症单核细胞中CCR 2表达的siRNA纳米颗粒。我们鉴定了一种优化的脂质纳米颗粒和沉默siRNA序列，当全身施用时，其具有快速的血液清除，在脾和骨髓中积累，并显示荧光标记的siRNA在单核细胞内的高细胞定位。单核细胞中CCR 2 mRNA的有效降解阻止了它们在炎症部位的积累。具体而言，该治疗减弱了动脉粥样硬化斑块中它们的数量，减少了冠状动脉闭塞后的梗死面积，延长了胰岛移植后糖尿病小鼠的正常血糖，并导致肿瘤体积减少和肿瘤相关巨噬细胞数量减少。总之，白细胞中siRNA纳米颗粒介导的CCR 2基因沉默选择性地调节先天免疫细胞亚型的功能，并可能允许开发特异性抗炎治疗。
Inflammatory monocytes -- but not the non-inflammatory subset -- depend on the chemokine receptor CCR2 for distribution to injured tissue and stimulate disease progression. Precise therapeutic targeting of this inflammatory monocyte subset could spare innate immunity's essential functions for maintenance of homeostasis and thus limit unwanted effects. Here we developed siRNA nanoparticles targeting CCR2 expression in inflammatory monocytes. We identified an optimized lipid nanoparticle and silencing siRNA sequence that when administered systemically, had rapid blood clearance, accumulated in spleen and bone marrow and showed high cellular localization of fluorescently tagged siRNA inside monocytes. Efficient degradation of CCR2 mRNA in monocytes prevented their accumulation in sites of inflammation. Specifically, the treatment attenuated their number in atherosclerotic plaques, reduced infarct size following coronary artery occlusion, prolonged normoglycemia in diabetic mice after pancreatic islet transplantation and resulted in reduced tumor volumes and lower numbers of tumor-associated macrophages. Taken together, siRNA nanoparticle-mediated CCR2 gene silencing in leukocytes selectively modulates functions of innate immune cell subtypes and may allow for the development of specific anti-inflammatory therapy.
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影响因子：
56.9
作者：
Peer, Dan;Park, Eun Jeong;Shimaoka, Motomu
通讯作者：
Shimaoka, Motomu
影响因子：
11.2
作者：
Movahedi, Kiavash;Laoui, Damya;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
DOI：
10.1097/01.asn.0000089563.63641.a8
发表时间：
2003-10-01
影响因子：
13.6
作者：
Furuichi, K;Wada, T;Yokoyama, H
通讯作者：
Yokoyama, H
影响因子：
4.8
作者：
Hart, Kevin M.;Bak, S. Peter;Berwin, Brent
通讯作者：
Berwin, Brent
影响因子：
37.8
作者：
Nahrendorf M;Pittet MJ;Swirski FK
通讯作者：
Swirski FK