Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity.

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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.

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Journal

Journal ID (iso-abbrev): Science

Title: Science (New York, N.Y.)

Publisher: American Association for the Advancement of Science (AAAS)

ISSN (Electronic): 1095-9203

ISSN (Print): 0036-8075

Publication date (Electronic): Nov 21 2014

Volume: 346

Issue: 6212

Affiliations

[1 ] Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.

[2 ] 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.

[3 ] Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.

[4 ] Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Angiogenesis Lab, Institute of Genetics and Biophysics, CNR, Naples, Italy.

[5 ] Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

[6 ] School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.

[7 ] Immunology Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada.

[8 ] Chapman University School of Pharmacy, 9401 Jeronimo Road, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA.

[9 ] Departments of Pathology and Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.

[10 ] Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA. jamba2@email.uky.edu.

Article

Mid ID: NIHMS649205 Publisher Item ID: 346/6212/1000

DOI: 10.1126/science.1261754

PMC ID: 4274127

PubMed ID: 25414314

SO-VID: 17dfbe4d-ab59-43f4-bedc-cb1b0657bc65

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