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Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity
Open accessAbstract
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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“The ensuing IFN-I and inflammatory responses were mitigated by treatment with NRTIs95, 129.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [129]
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“Another possibility is the reported anti-inflammatory property of NRTIs to alleviate activation of the NLRP3 inflammasome without engaging reverse transcriptase129.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [129]
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Metadata
- 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
- Venue
- Science
- Published
- 2014-11-21
- Volume
- 346
- Issue
- 6212
- Pages
- 1000-1003
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- 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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