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

Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

Open access
Fowler, Benjamin J., Gelfand, Bradley D., Kim, Younghee, Kerur, Nagaraj, Tarallo, Valeria, Hirano, Yoshio, Amarnath, Shoba, Fowler, Daniel H. +14 more·2014·Science

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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  • The ensuing IFN-I and inflammatory responses in AMD were mitigated by treatment with NRTIs.

    “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]

    The paper reports that NRTIs blocked Alu RNA–induced inflammasome activation, IL-18 maturation, and retinal degeneration in AMD-related models (section labeled Abstract; page unavailable). It does not report mitigation of type I interferon (IFN-I) responses in AMD. Its reported reduction in IFN-γ concerns a graft-versus-host disease model, not AMD; IFN-γ is not IFN-I. (LLM, conf=0.87)

    Experimental — accuracy not yet measured
  • NRTIs possess an anti-inflammatory action that reduces NLRP3 inflammasome activation independently of reverse transcriptase engagement.

    “Another possibility is the reported anti-inflammatory property of NRTIs to alleviate activation of the NLRP3 inflammasome without engaging reverse transcriptase129.”

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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
Venue
Science
Published
2014-11-21
Volume
346
Issue
6212
Pages
1000-1003
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
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
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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