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 Yasuma; Charles Wright; Jayakrishna Ambati

doi:10.1126/science.1261754

Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

Science. 2014 Nov 21;346(6212):1000-3. doi: 10.1126/science.1261754.

Authors

Benjamin J Fowler¹, Bradley D Gelfand², Younghee Kim³, Nagaraj Kerur³, Valeria Tarallo⁴, Yoshio Hirano³, Shoba Amarnath⁵, Daniel H Fowler⁵, Marta Radwan⁶, Mark T Young⁶, Keir Pittman⁷, Paul Kubes⁷, Hitesh K Agarwal⁸, Keykavous Parang⁸, David R Hinton⁹, Ana Bastos-Carvalho³, Shengjian Li³, Tetsuhiro Yasuma³, Takeshi Mizutani³, Reo Yasuma³, Charles Wright³, Jayakrishna Ambati¹⁰

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alu Elements
Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Apoptosis / drug effects
Carrier Proteins / metabolism
Caspase 1 / metabolism
Choroidal Neovascularization / drug therapy
Disease Models, Animal
Geographic Atrophy / drug therapy
Graft vs Host Disease / drug therapy
Hepatitis / drug therapy
Inflammasomes / drug effects*
Liver / drug effects
Mice
NLR Family, Pyrin Domain-Containing 3 Protein
Receptors, Purinergic P2X7 / metabolism
Retinal Pigment Epithelium / drug effects
Retinal Pigment Epithelium / metabolism
Retinal Pigment Epithelium / physiology
Reverse Transcriptase Inhibitors / pharmacology*
Reverse Transcriptase Inhibitors / therapeutic use

Substances

Anti-Inflammatory Agents, Non-Steroidal
Carrier Proteins
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 protein, human
Receptors, Purinergic P2X7
Reverse Transcriptase Inhibitors
Caspase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding