Journal Article

Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

Gelfand, Bradley D., Radwan, Marta, Mizutani, Takeshi, Wright, Charles, Fowler, Benjamin J., Hinton, David R., Yasuma, Tetsuhiro, Kubes, Paul, Agarwal, Hitesh K., Tarallo, Valeria, Parang, Keykavous, Kerur, Nagaraj, Amarnath, Shoba, Yasuma, Reo, Pittman, Keir, Fowler, Daniel H., Young, Mark T., Ambati, Jayakrishna, Li, Shengjian, Kim, Younghee, Hirano, Yoshio, Bastos-Carvalho, Ana

2014

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Activation / Alu Elements / angiogenesis / animal models / Animals / anti-inflammatory activity / Anti-Inflammatory Agents, Non-Steroidal - pharmacology / Anti-Inflammatory Agents, Non-Steroidal - therapeutic use / Apoptosis - drug effects / Atrophy / Blocking / Carrier Proteins - metabolism / Caspase 1 - metabolism / caspase-1 / Cell death / Choroidal Neovascularization - drug therapy / Disease Models, Animal / Dosage / Drug therapy / Drugs / epithelium / Geographic Atrophy - drug therapy / Graft vs Host Disease - drug therapy / Grafting / HEK293 cells / Hepatitis - drug therapy / HIV / Human immunodeficiency virus / Inflammasomes - drug effects / inflammation / Inhibitor drugs / Inhibitors / liver / Liver - drug effects / Macular degeneration / Medical research / Mice / Narcotics / NLR Family, Pyrin Domain-Containing 3 Protein / Nucleosides / Phosphorylation / Receptors, Purinergic P2X7 - metabolism / Research grants / Retinal Pigment Epithelium - drug effects / Retinal Pigment Epithelium - metabolism / Retinal Pigment Epithelium - physiology / Reverse Transcriptase Inhibitors - pharmacology / Reverse Transcriptase Inhibitors - therapeutic use / Ribonucleic acid / Ribonucleic acids / RNA / RNA-directed DNA polymerase / T lymphocytes / therapeutics / Transfection