Cited by 225Inflammasome and immune disordersAdenosine and Purinergic SignalingOcular Diseases and Behçet’s Syndrome

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Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

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Fowler, Benjamin J., Gelfand, Bradley D., Kim, Younghee, Kerur, Nagaraj, Tarallo, Valeria, Hirano, Yoshio, Amarnath, Shoba, Fowler, Daniel H., Radwan, Marta, Young, Mark T., Pittman, Keir, Kubes, Paul, Agarwal, Hitesh K., Parang, Keykavous, Hinton, David R., Bastos-Carvalho, Ana, Li, Shengjian, Yasuma, Tetsuhiro, Mizutani, Takeshi, Yasuma, Reo, Wright, Charles, Ambati, Jayakrishna·2014·Science

DOI 10.1126/science.1261754PMC PMC4274127

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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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Authors: Fowler, B. J., Gelfand, B. D., Kim, Y., Kerur, N., Tarallo, V., Hirano, Y., Amarnath, S., Fowler, D. H., Radwan, M., Young, M. T., Pittman, K., Kubes, P., Agarwal, H. K., Parang, K., Hinton, D. R., Bastos-Carvalho, A., Li, S., Yasuma, T., Mizutani, T., Yasuma, R., Wright, C., & Ambati, J.
Affiliations: University of Kentucky (US)
National Institutes of Health (US)
Cardiff University (GB)
University of Calgary (CA)
Chapman University (US)
University of Southern California (US)
Corresponding author: Ambati, Jayakrishna
ORCID: Fowler, Benjamin J.
Gelfand, Bradley D.
Kerur, Nagaraj
Tarallo, Valeria
Hirano, Yoshio
Amarnath, Shoba
Young, Mark T.
Kubes, Paul
Agarwal, Hitesh K.
Parang, Keykavous
Hinton, David R.
Yasuma, Tetsuhiro
Yasuma, Reo
Ambati, Jayakrishna
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2014-11-21
Volume: 346
Issue: 6212
Pages: 1000-1003
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1261754
PMC: PMC4274127
OpenAlex: W2058803210
Cited by: 225
References: 48
Citations by year: 2026: 11 · 2025: 13 · 2024: 15 · 2023: 17 · 2022: 19 · 2021: 24 · 2020: 16 · 2019: 20 · 2018: 19 · 2017: 26 · 2016: 21 · 2015: 23 · 2014: 1
FWCI: 9.71
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Science (publishedVersion)
PubMed (publishedVersion)
ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Chapman University Digital Commons (Chapman University) (submittedVersion)
ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
Funders: National Institutes of Health (TL1TR000115, 1ul1rr033173-01, UL1TR000117)
Biotechnology and Biological Sciences Research Council (BB/J017345/1)
National Heart, Lung, and Blood Institute (T32HL091812)
National Eye Institute (R01EY020672, P30EY003040, R01EY018836, R01EY001545, R01EY018350, R00EY024336, R01EY024068, R01EY022238, K99EY024336)
National Institute of General Medical Sciences (DP1GM114862)
National Center for Research Resources (UL1RR-033173, TL1RR033172)
National Center for Chronic Disease Prevention and Health Promotion (DP1GM114862)
National Center for Advancing Translational Sciences
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
Keywords: nucleoside reverse transcriptase inhibitors, anti-inflammatory activity, P2X7 receptor, NLRP3 inflammasome, Alu RNA, geographic atrophy, age-related macular degeneration, retinal pigment epithelium, caspase-1 activation, choroidal neovascularization, graft-versus-host disease, drug repurposing, HIV treatment
MeSH terms: NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Anti-Inflammatory Agents, Non-Steroidal, Carrier Proteins, Disease Models, Animal, Graft vs Host Disease, Hepatitis, Liver, Apoptosis, Reverse Transcriptase Inhibitors, Alu Elements, Caspase 1, Choroidal Neovascularization, Mice, Retinal Pigment Epithelium, Geographic Atrophy, Receptors, Purinergic P2X7, Inflammasomes

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Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

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