Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity
| Autor: | David R. Hinton, Shoba Amarnath, Takeshi Mizutani, Bradley D. Gelfand, Ana Bastos-Carvalho, Benjamin J. Fowler, Hitesh K. Agarwal, Valeria Tarallo, Charles B. Wright, Reo Yasuma, Shengjian Li, Marta Radwan, Nagaraj Kerur, Paul Kubes, Tetsuhiro Yasuma, Younghee Kim, Keykavous Parang, Keir Pittman, Yoshio Hirano, Jayakrishna Ambati, Daniel H. Fowler, Mark T. Young |
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| Rok vydání: | 2014 |
| Předmět: |
RM
Inflammasomes Caspase 1 Graft vs Host Disease Alu element Apoptosis Retinal Pigment Epithelium Biology Hepatitis Nucleoside Reverse Transcriptase Inhibitor QH301 Mice Retrovirus Alu Elements immune system diseases Geographic Atrophy NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Multidisciplinary Effector Anti-Inflammatory Agents Non-Steroidal virus diseases RNA Inflammasome biology.organism_classification Virology Choroidal Neovascularization Reverse transcriptase Disease Models Animal Liver Cancer research Reverse Transcriptase Inhibitors Receptors Purinergic P2X7 Carrier Proteins medicine.drug |
| Zdroj: | Science. 346:1000-1003 |
| ISSN: | 1095-9203 0036-8075 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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