核苷类逆转录酶抑制剂具有内在的抗炎活性。
Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity.
作者信息
Fowler Benjamin J, Gelfand Bradley D, Kim Younghee, Kerur Nagaraj, Tarallo Valeria, Hirano Yoshio, Amarnath Shoba, Fowler Daniel H, Radwan Marta, Young Mark T, Pittman Keir, Kubes Paul, Agarwal Hitesh K, Parang Keykavous, Hinton David R, Bastos-Carvalho Ana, Li Shengjian, Yasuma Tetsuhiro, Mizutani Takeshi, Yasuma Reo, Wright Charles, Ambati Jayakrishna
机构信息
Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.
Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Microbiology, Immunology, and Human Genetics, University of Kentucky, Lexington, KY 40536, USA. Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40536, USA.
出版信息
Science. 2014 Nov 21;346(6212):1000-3. doi: 10.1126/science.1261754.
Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)-derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.
核苷类逆转录酶抑制剂（NRTIs）是治疗HIV的主要药物，可阻断逆转录病毒复制。Alu（一种内源性逆转录元件，其生命周期也需要逆转录酶）衍生的RNA激活P2X7和NLRP3炎性小体，导致地图样萎缩（一种年龄相关性黄斑变性）中视网膜色素上皮细胞死亡。我们发现，NRTIs可独立于逆转录酶抑制作用，抑制P2X7介导的NLRP3炎性小体激活。多种已获批且具有临床相关性的NRTIs可预防由Alu RNA诱导的半胱天冬酶-1激活，而半胱天冬酶-1是NLRP3炎性小体的效应因子。NRTIs在地图样萎缩、脉络膜新生血管、移植物抗宿主病和无菌性肝脏炎症的小鼠模型中均有效。我们的研究结果表明，NRTIs在P2X7驱动的疾病中进行药物重新利用的时机已经成熟。
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