Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1000-1003
Number of pages4
JournalScience
Volume346
Issue number6212
DOIs
StatePublished - Nov 21 2014
Externally publishedYes

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity'. Together they form a unique fingerprint.

Cite this